Muscular Dystrophy Vignette

Question 1

Hypertrophic Cardiomyopathy

Answer 1

a) Phenotype:
HCM: autosomal dominant (lots of genetic heterogeneity); wall of heart is too stiff. Incomplete penetrance. Most common explanation for young athletes who die suddenly. We see cardiomyocyte and cardiac hypertrophy  organ hypertrophy. Myocyte disarray  functionally compromised. Interstitial and replacement fibrosis  propensity for arrhythmia. Dysplastic intramyocardial arterioles  ischemia. Majority of people are asymptomatic, but some have dyspnea, angina, and syncope. Some experience sudden cardiac death, and some die suddenly. May have cardiac murmur, pump failure, arrhythmia.

b) Molecular defect causing the abnormal muscle cell phenotype:

HCM: mainly a disease of the sarcomere. There are mutations in the genes coding for the proteins in the sarcomere. Generally the protein isn’t missing, but it has an AA change that decreases protein function. Majority of mutations are missense mutations in structural genes. (Secondary causes = HTN, aortic valve disease, congenital heart disease, and obesity).

Question 2

Malignant Hyperthermia

Answer 2

a) Phenotype:
Malignant Hyperthermia: autosomal dominant. Once exposed to anesthesia (halothane or succinylcholine), experience hypermetabolism, skeletal muscle damage, hyperthermia  death if untreated.

b) Molecular defect causing the abnormal muscle cell phenotype:
Malignant hyperthermia: AD, due to mutations in the RYR1 Ca channel on the SR. More of an environmental disorder since it only expresses a phenotype when one has been exposed to anesthesia (halothane or succinylcholine). RYR1 channel on SR activated in response to anesthetics and stays open  sustained muscle activation/contraction, increased aerobic/anaerobic metabolism, increased heat production  muscle hypoxia and death.
-MH syndrome = metabolic/respiratory acidosis, muscular rigidity, hyperthermia, and rhabdomylosis (muscle breakdown). Increased CO2 production as well.
-can sometimes recognize via masseter spasms
-can test by doing a halothane/caffeine test on muscle biopsy.

c) Know the triggers and treatment of malignant hyperthermia
volatitle anestetics halothane 1/15000
reduce mortalitiy with IV dantrline. blocks ca release from SR

Triggers = halothane and succinylcholine anesthetic agents, mainly – or other volatile anesthetics. 
Treatment = DANTROLENE sodium  shuts down the whole process. Can manage by stopping anesthesia, hyperventilating with O2, bicarb, cooling the patient, and treating arrhythmia.

Question 3

Duchenne Muscular Dystrophy:

Answer 3

a) Phenotype:
DMD: Decreased musculature, calf hypertrophy, Gower’s sign, no dystrophin protein due to mutation in DMD gene. Abnormal gait, high creatine kinase, maybe some intellectual disability. Will probably need a wheelchair; death generally due to cardiopulmonary issues (cardiomyopathy common).

b) Molecular defect causing the abnormal muscle cell phenotype:
DMD: X-linked. Due to a mutation that causes you to make no dystrophin protein (large protein associated with actin in the PM and the surface membrane  links cytoskeleton with ECM. DMD due to big deletions or frameshift. Becker MD  due to small, in-frame deletions so you still have some dystrophin, and milder symptoms. Treat with support, leg braces, steroids to prolong ambulation. Trying targeted therapy with growth-modulating agents (myostatin), anti-inflammatories, antisense oligos with exon skipping, agents that suppress stop codon mutations, and cell-based therapies (myoblasts/stem cells).

2. Describe the potential role of manipulation of myostatin function in the treatment of muscular dystrophies.

Mature muscle cells can’t divide, but they can increase in length and girth by recruiting myoblasts and increasing in size/number of myofibrils (increase sarcomeres).
Myostatin = muscle growth regulator/inhibitor  secreted by muscle cells as negative feedback for muscle growth. If you could inhibit myostatin, maybe people with MD’s would lose less muscle mass?