Biochemistry

Question 1

What is the most common type of muscular dystrophy?

Answer 1

Duchenne Muscular Dystrophy (DMD)

Question 2

What is the second most common type of muscular dystrophy?

Answer 2

Myotonic Dystrophy

Question 3

What is the third most common type of muscular dystrophy?

Answer 3

Facioscapulohumeral Dystrophy

Question 4

DMD- inheritance

Answer 4

X-linked recessive

Question 5

DMD- mutation

Answer 5

Dystrophin gene

Question 6

What is significant about the size of the dystrophin gene on the X chromosome?

Answer 6

It is the largest known human gene (2.4 million base pairs)

Question 7

In DMD, how much of the dystrophin is missing?

Answer 7

99%

Question 8

What types of mutations occur in 60% of DMD pts?

Answer 8

deletions

Question 9

What other mutations can DMD pt’s have in the dystrophin gene?

Answer 9

duplications (~6% of pt’s), and other subtle mutations

Question 10

What is the role of dystrophin in the skeletal muscle cell?

Answer 10

joins the intracellular cytoskeleton to the extracellular matrix. It interacts with actin and β-dystroglycan

Question 11

DMD- pathogenesis

Answer 11

relatively normal at birth but show impared muscle fxn by the time they begin to walk, patients are in a wheelchair by age 10 and survive until their late teens or early twenties

Question 12

What is significant about the calf muscles in DMD pts?

Answer 12

calf muscles gain fat and connective tissue instead of muscle

Question 13

What % of DMD pt’s have a low IQ?

Answer 13

~25%

Question 14

What serum protein is high in DMD pts?

Answer 14

Creatinine Kinase (CK)

Question 15

DMD- Dx

Answer 15

DNA analysis (PCR) for carrier deletion

Question 16

Becker’s Muscular Dystrophy (BMD)- inheritance

Answer 16

X-linked recessive

Question 17

Is BMD more or less severe than DMD?

Answer 17

about 10x less severe

Question 18

BMD- mutation

Answer 18

Dystrophin is reduced or altered in size. From non-frameshift mutations in gene.

Question 19

BMD- pathogenesis

Answer 19

Occurs later in life (~11 y/o) with a slower progression than DMD, a small minority never lose the ability to walk.

Question 20

Myotonic Muscular Dystrophy (MMD)- inheritance

Answer 20

Autosomal dominant

Question 21

MMD1- mutation

Answer 21

trinucleotide repeat of CTG in the DMPK gene

Question 22

MMD2- mutation

Answer 22

CCTG repeat on CNBP gene.

Question 23

What is the role of the DMPK enzyme in MMD1 mutations?

Answer 23

This regulates signal transduction and Ca-ion flux in the skeletal muscle, heart and brain

Question 24

What is the role of the CNBR enzyme in MMD2 mutations?

Answer 24

encodes a zinc finger protein, whose role is unclear

Question 25

In MMD2 mutations, is there a correclation between size of expansion and age of onset or severity?

Answer 25

Nope

Question 26

MMD1- pathogenesis

Answer 26

Most common form of muscular dystrophy in adults (1/8000), signs do not appear until after adolescence and progression is slow. Generation-to-generation it appears earlier and more severe (anticipation).

Question 27

MMD1- clinical presentation

Answer 27

Muscle wasting (mask-like face), myotonia, cataracts, diabetes, testicular atrophy and sometimes mental retardation.

Question 28

MMD- Dx

Answer 28

Dx by PCR or Southern blot of repeat sequence.

Question 29

Facioscapulohumeral Dystrophy (FD)- inheritance

Answer 29

Autosomal dominant

Question 30

FD- mutation

Answer 30

Gene is on long arm of chromosome 4 but protein product is yet to be isolated and characterized

Question 31

FD- pathogenesis

Answer 31

Affects the upper body (lol look at the name) unlike DMD or BMD. Sx are variable in age on onset, extent and severity. Ususally cocurs between 10-25 y/o. Sx progress slowly and life expectancy is normal, although ~20% are wheelchair bound

Question 32

FD- clinical features

Answer 32

Facial and upper arm muscle weakness, may progress to legs

Question 33

Limb-girdle Muscular Dystrophies (LGMD)- inheritance

Answer 33

Both autosomal dominant and recessive

Question 34

Dominant LGMD- onset

Answer 34

adulthood

Question 35

Recessive LGMD- onset

Answer 35

childhood/teen years

Question 36

Dominant LGMD- mutation

Answer 36

affect various muscle proteins.

Question 37

recessive LGMD- mutation

Answer 37

genes encoding the 4 sarcoglycans (α, β, γ and δ)

Question 38

LGMD- clinical features

Answer 38

Group of disorders characterized by muscle weakness affecting both arms and legs. Progression is varied.

Question 39

Bethlem Myopathy (BM)- inheritance

Answer 39

Autosomal Dominant. Rare.

Question 40

BM- mutation

Answer 40

Mutations in chromosome 21 genes encoding Type VI Collagen.

Question 41

BM- onset

Answer 41

before 5 y/o

Question 42

BM- clinical features

Answer 42

Proximal muscle weakness affecting both legs and arms, joint contractures in ankles and elbows.

Question 43

Oculopharyngeal Muscular Dystrophy (OPMD)- inheritance

Answer 43

Autosomal Dominant.

Question 44

OPMD- mutation

Answer 44

Expansion of a GCN repeat within the PABPN1 (Poly-A binding protein) gene.

Question 45

What happens to the PABN1 protein when the GCN repeat is expanded in OPMD?

Answer 45

Extra AA's cause the protein to clump in the nuclei

Question 46

OPMD- onset

Answer 46

later in life (40-50)

Question 47

OPMD- clinical features

Answer 47

Drooping eyelids and weakness in facial pharyngeal muscles, but can extend to limbs.

Question 48

What types of populations is OPMD frequent in?

Answer 48

Most common in French-Canadian families (1/1000) Bukharan Jews in Israel (1/600).

Question 49

Malignant Hyperthermia (MH)- cause

Answer 49

A severe reaction to certain anesthetics and depolarizing skeletal muscle relaxants. There is a pathological elevation in Ca ions in the sarcoplasm.

Question 50

MH- mechanism of injury

Answer 50

Opening of defective Ca release channel is prolonged --> Ca ions flood sarcoplasm --> myosin ATPase activated --> Ca-ATPase pumps work maximally and try to pump Ca back into SR --> ATP in consumed rapidly --> ATP, CO2 and heat are made by glycogen metabolism --> muscle rigidity, heat production and acidosis.

Question 51

MH- Sx

Answer 51

Muscle rigidity, hyperthermia, acidosis and tachycardia.

Question 52

How can MH be treated?

Answer 52

They used to be fatal but dantrolene (which inhibits Ca++ release from the SR) combats it. This reduces it to ~10%.

Question 53

What is anticipation?

Answer 53

if a heritable repeat expansion disorder occurs earlier and more severe as lineages progress, the next individual can “anticipate” the disease having a larger severity and onset at an earlier age