Genetics of Muscular Dystrophy (Week 4--Cederbaum)

Question 1

Dystrophin-Glycoprotein complex at the cell membrane

Answer 1

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

Question 2

Myofibers

Answer 2

Elongated multinucleated cells that comprise skeletal muscle

Peripherally located myonuclei

Sarcolemma with dystrophin underneath

Basal lamina with laminin, collagen IV, fibronectin

Question 3

After you get a history and determine the CPK or CK, what do you do next?

Answer 3

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

Question 4

Human exome

Answer 4

30 million bases, 1% of the genome

20,000 genes and 240,000 exons

Only capture the regions of the genome of interest

Question 5

Duchenne’s Muscular Dystrophy (DMD)

Answer 5

X-linked recessive mutation in dystrophin gene

“Jerry’s Kids”

Severe muscle disorder with progressive clinical course and no effective treatment at this time

Question 6

Early history in boys with DMD

Answer 6

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

Question 7

Muscle pseudohypertrophy in DMD

Answer 7

Muscles appear hypertrophied but are weak

Muscle tissue replaced with connective tissue and fat

Question 8

Gowers maneuver

Answer 8

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

Question 9

Early clinical lab finding in DMD

Answer 9

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

Question 10

Later history in boys with DMD

Answer 10

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)

Question 11

Cardiac involvement in DMD

Answer 11

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

Question 12

MR/DD in patients with DMD

Answer 12

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

Question 13

Becker Muscular Dystrophy (BMD)

Answer 13

Also due to mutations in dystrophin gene

Milder phenotype than DMD

Still ambulatory at 16 years

Question 14

CPK or CK

Answer 14

Creatine phosphokinase is a muscule protein and it leaks if muscle is damaged

Question 15

DMD vs. BMD

Answer 15

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

Question 16

Mutation rate of dystrophin gene

Answer 16

1 in 10,000 which is high

Question 17

Inheritance of DMD and BMD

Answer 17

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

Question 18

Female carriers for DMD

Answer 18

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)

Question 19

DMD gene and its product

Answer 19

Large!

Gene is structurally complex (79 exons, 7 tissue-specific promoters)

Differential splicing, so numerous isoforms (tissue-specific isoforms and developmentally regulated isoforms)

Question 20

Where is dystrophin most abundant?

Answer 20

Skeletal muscle

Cardiac muscle

Brain

But most tissues express at least one isoform

Question 21

Are DMD mutations deletions or point mutations?

Answer 21

60% deletions

34% point mutations

Question 22

Therapy for DMD

Answer 22

Corticosteroids can delay onset of wheel chair need for 2 years

Isolation and characterization of DMD gene gave promise for effective therapeutics

Question 23

Prenatal testing showed that mother was not a carrier but she still had a son with DMD, what happened?

Answer 23

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