Muscular Dystrophy Vignette

Question 1

What is the phenotype for patients with Hypertrophic cardiomyopathy?

Answer 1

Asymptomatic throughout life, but some have dyspnea, angina, and syncope or experience sudden cardiac death

Question 2

What is the phenotype for patients with Malignant hyperthermia?

Answer 2

Hypermetabolism, skeletal muscle damage, hyperthermia, death if untreated (~70% mortality untreated)

Question 3

What is the phenotype for patients with Duchenne Muscular Dystrophy?

Answer 3

Muscle weakness, cardiomyopathy

Question 4

What are the triggers for MH?

Answer 4

Potent volatile anesthetics including Halothane and Succinylcholine

Question 5

What is the treatment for MH?

Answer 5

Administration of intravenous Dantrolene 2.5mg/kg, hyperventilation with 100% Oxygen, bicarbonate as needed, cool patient, treat arrhythmias without Ca++ channel blockers

Question 6

What is the molecular defect in Hypertrophic cardiomyopathy?

Answer 6

Missense mutation in structural genes of muscle fibers

Question 7

What is the molecular defect in Malignant hyperthermia?

Answer 7

Ryanodine 1 Receptor (RyR) in Ca++ channels mutates to allow Ca++ to flow continuously through to sarcoplasmic reticulum. Much ATP spent pumping Ca++ back out, generating heat in a futile cycle.

Question 8

What is the molecular defect in Duchenne Muscular Dystrophy?

Answer 8

Mutation on X-chromosome in the dystrophin gene leads to non-functional dystrophin protein, a structural component of muscle cells in the dystroglycan complex of the cell membrane

Question 9

What is the physiology of Malignant hyperthermia?

Answer 9

Due to a defect in the Ryanodine receptor, Ca++ floods into muscle cells in the presence of certain anesthetics. The increased intracellular Ca++ triggers muscle contraction. Muscle contraction burns ATP via actin-myosin interaction and Ca++ pump back to sarcomere. Much heat generated in futile cycle as Ca++ just floods back into the muscle cell through the open Ca++ channel from the SR, due to RyR defect.

Question 10

What is the potential role of myostatin function manipulation in the treatment of muscular dystrophies?

Answer 10

Clinical trials, such as for treatment in Intensive Care Unit Acquired Paresis (ICUAP)
May treat with agents that suppress stop codon mutations or antisense oligonucleotides w/ exon-skipping capacity

Question 11

What is myostatin?

Answer 11

Myostatin is a muscle growth regulator, specifically an inhibitor

Question 12

What is the function of myostatin?

Answer 12

Negative feedback mechanism to inhibit muscle growth

Question 13

What is the inheritance pattern for HCM?

Answer 13

Autosomal dominant with incomplete penetrance

Question 14

What is the cellular phenotype for patients with Hypertrophic cardiomyopathy?

Answer 14

Sarcomere mutation leading to:

1) cardiomyocyte and cardiac hypertrophy -> organ hypertrophy
2) myocyte disarray -> function compromised
3) interstitial and replacement fibrosis -> propensity to arrhythmia
4) dysplastic intramyocardial arterioles -> ischemia

Question 15

What are the clinical presentations for a patient with HCM?

Answer 15

1) cardiac murmur (if LV outflow obstruction)
2) cardiac pump failure (dyspnea, angina)
3) arrhythmia (syncope/sudden death)
4) sports/family screening

Question 16

What is the median age of death for an athletic patient with HCM?

Answer 16

17 years old

Question 17

What is the cellular phenotype for patients with DMD?

Answer 17

Big deletions, frameshift mutations

Becker Type is smaller, in-frame deletions

Question 18

What are the clinical presentations for a patient with DMD?

Answer 18

Onset of skeletal muscle disease ages 3-5 years
Abnormal gait, toe-walking
Gowers' sign
Calf pseudohypertrophy
High creatinine kinase (1000s)
Cardiomyopathy 100% by 18 years
Reproductive fitness ~0

Question 19

What is the inheritance pattern for DMD?

Answer 19

X-linked

Question 20

What is the phenotype in cases of myostatin deficiency?

Answer 20

Massive muscularization - Belgian Blue Cattle, Mighty Mouse, East German Olympic athletes from the 1970s…

Question 21

Where is myostatin produced?

Answer 21

Muscle cells make and secrete myostatin

Question 22

How would a patient with excessive myostatin present?

Answer 22

Muscles wasted, may be raised in AIDS patients

Question 23

What is the Mighty Mouse gene?

Answer 23

The gene that encodes for myostatin

Question 24

What is the clinical presentation of MH?

Answer 24

Muscle rigidity (masseter spasm)
Increased CO2 production
Rhabdomyolysis
Hyperthermia

Question 25

What anesthetics will not trigger MH?

Answer 25

Intravenous agents
Opioids
Non-depolarizing agents
Ketamine
Propofol
Anxiolytics

Question 26

What is the inheritance pattern for MH?

Answer 26

The MH1-3 defects in RyR gene are inherited as autosomal dominant with limited penetrance

Question 27

What test can signal potential MH complication?

Answer 27

Halothane/Caffeine test on muscle biopsy

Question 28

Other than genetic missense mutation affecting muscle structure, what are secondary causes of HCM?

Answer 28

Hypertension, aortic valve disease, congenital heart disease, obesity, etc.