Genetics of Muscular Dystrophy (Week 4--Cederbaum) Flashcards
Dystrophin-Glycoprotein complex at the cell membrane
Complex structure that pulls muscle membrane together and is responsible for actions of muscle
Spectrin repeats in this molecule, and molecule can still function if some repeats are missing
Myofibers
Elongated multinucleated cells that comprise skeletal muscle
Peripherally located myonuclei
Sarcolemma with dystrophin underneath
Basal lamina with laminin, collagen IV, fibronectin
After you get a history and determine the CPK or CK, what do you do next?
Used to be that you take a muscle biopsy
These days, we do DNA analysis because it is not disfiguring and does not require general anesthesia
Human exome
30 million bases, 1% of the genome
20,000 genes and 240,000 exons
Only capture the regions of the genome of interest
Duchenne’s Muscular Dystrophy (DMD)
X-linked recessive mutation in dystrophin gene
“Jerry’s Kids”
Severe muscle disorder with progressive clinical course and no effective treatment at this time
Early history in boys with DMD
Appear normal for first 1-2 years of life
In retrospect, many have delayed walking beyond 18 months
Muscle weakness recognized at 3-5 years of age
Difficulties noted with rising from seated position esp from floor, and climbing stairs
Muscle pseudohypertrophy in DMD
Muscles appear hypertrophied but are weak
Muscle tissue replaced with connective tissue and fat
Gowers maneuver
Classical maneuver that boys with DMD independently discover and use by age 5
Illustrates progressive myopathy (begins with hip girdle muscles and neck flexors and progresses to shoulder girdle then muscles of distal limbs and trunk)
Uses limb muscles to “climb up legs” to standing position
This common solution to weakness indicates that pattern of progression is similar among boys affected with DMD
Early clinical lab finding in DMD
In preclinical and early stages of DMD
Serum creatine kinase (CK or CPK) dramatically increased (50-100x normal) due to release from breakdown of diseased muscle
Later history in boys with DMD
Usually confined to wheelchair by 12 years old
Survival beyond 20 unlikely
Median age at death is 18
Die of skeletal or cardiac muscle involvement (respiratory failure, pneumonia, cardiac failure)
Cardiac involvement in DMD
95% have cardiac compromise (dilated cardiomyopathy and/or abnormal EKG)
84% have cardiac findings at autopsy
50% have chronic cardiac failure
May present rarely with heart failure
MR/DD in patients with DMD
Statistics on MR/DD (mental retardation) in boys with DMD are somewhat misleading
Average IQ reduced 10-20 points
30% have some degree of MR/DD
There was a tendency to overlook this since so much of focus was on physical disability
Dystrophin expressed in brain and therefore MR/DD attributed to reduced brain expression
Becker Muscular Dystrophy (BMD)
Also due to mutations in dystrophin gene
Milder phenotype than DMD
Still ambulatory at 16 years
CPK or CK
Creatine phosphokinase is a muscule protein and it leaks if muscle is damaged
DMD vs. BMD
DMD: 85% of DMD mutations; mutations result in absence or near absence of dystrophin
BMD: 15% of DMD mutations; mutations usually frame deletions so maintain dystrophin expression but a shorter protein and at reduced levels
Mutation rate of dystrophin gene
1 in 10,000 which is high
Inheritance of DMD and BMD
Both X-linked recessive
DMD: genetic lethal in males, 1/3 cases due to new mutations, 2/3 cases have carrier mothers
BMD: genetic fitness up to 70% of normal; high proportion of BMD cases inherited and only 10% due to new mutations
Female carriers for DMD
Majority have no clinical manifestations
70% have slightly increased serum CK
Normal X chromosome inactivated in critical proportion of cells in some (8% have significant muscle weakness, some with severe proximal muscle impairment)
DMD gene and its product
Large!
Gene is structurally complex (79 exons, 7 tissue-specific promoters)
Differential splicing, so numerous isoforms (tissue-specific isoforms and developmentally regulated isoforms)
Where is dystrophin most abundant?
Skeletal muscle
Cardiac muscle
Brain
But most tissues express at least one isoform
Are DMD mutations deletions or point mutations?
60% deletions
34% point mutations
Therapy for DMD
Corticosteroids can delay onset of wheel chair need for 2 years
Isolation and characterization of DMD gene gave promise for effective therapeutics
Prenatal testing showed that mother was not a carrier but she still had a son with DMD, what happened?
Gonadal mutation in the mother
Mother’s eggs had DMD mutation early in oogenesis so even though she does not have the mutation in her somatic cells, a lot of her eggs have this mutation
