Biochemical Basis of Some Muscle Disorder

Question 1

Duchenne

Answer 1

1/3500 males
30% due to new mutations
Most severe is MDs
Frameshift mutation
Absent Dystrophin
Rapid progression, wheelchair age 10, death in teens
Positive Gower's sign
CK Markedly elevated 50-100 times normal

Question 2

Becker Muscular Dystrophy

Answer 2

1/20,000 males
<2% new mutation
Less severe with slower progression than DMD, later onset
Reduced dystrophin levels or modified
Point mutation
CK mildly elevated

Question 3

DM1 Myotonic Muscular Dystrophy

Answer 3

98% expansion of CTG repeats in non-coding region of DMPK gene
Chromosome 19
Shows anticipation
Generally suffer only from cataracts and mild myotonia
Congenital DM1 is particularly severe
50% patients suffer from mental retardation

Question 4

DM2 Myotonic Muscular Dystrophy

Answer 4

Expansion of CCTG repeat in non-coding region of CNBP (ZNF9, zinc finger) gene
Chromosome 3

Question 5

Myotonic Muscular Dystrophy MMD or DM

Answer 5

most common form of muscular dystrophy affecting adults (most with DMD die young)
1/8,000
Multisystem disorder affects heart, smooth muscle, CNS, eye, endocrine glands
Shows anticipation
Myotonia, muscle wasting, cataracts, diabetes mellitus, frontal balding, mild mental deterioration, testicular atrophy

Question 6

SCAIP

Answer 6

Single condition amplification/internal primer sequencing

Question 7

MMD or DM

Answer 7

Autosomal dominant
Most common form of muscular dystrophy affecting adults ~1 in 8000
Multisystem disorder-also affects heart, smooth muscle, CNS, eye, endocrine gland
Frequently appears after adolescence (slow progression)
Tendency for earlier and more severe expression from generation to generation

Question 8

ANTICIPATION

Answer 8

Tendency for earlier and more severe expression from generation to generation

Question 9

Myotonic Muscular Dystrophy

Answer 9

Myotonia
Muscle wasting
Cataracts
Diabetes Mellitus
Frontal balding
Mild mental deterioration
Testicular atrophy
Targeted mutation analysis 
PCR using primers flanking the repeat sequence
Southern blotting (larger expansions)

Question 10

Facioscapulohumeral Dystrophy

Answer 10

Autosomally dominant
1/20,000
Principally upper body
Genetic defect on long arm of chromosome 4
Usually have normal life span (onset 10-25 years)
CK levels normal to 5 fold increase

Question 11

LGMD

Answer 11

Range of mutations in different proteins
Autosomally dominant and recessive
Recessive more common with earlier onset (1st/2nd decade)
Weakness in upper arms/legs
4 of most common forms mutations in genes encoding sarcoglycans (alpha, beta, gamma, delta)
CK levels normal to very high

Question 12

OPMD

Answer 12

Oculopharyngeal muscular dystrophy
Autosomal dominant rarely recessive
GCN repeat in gene encoding poly(A) binding protein PABPN1
Molecules clump in cell nuclei
Drooping eyelids, weakness in facial and pharyngeal muscles, can extend limbs
Onset 5/6th decade
Relatively rate 1/100,000
CK levels normal or midly elevated
1/1000 French-Canadiens; 1/600 Bukharan Jews, Hispanics in northern NM

Question 13

CMD

Answer 13

Congenital muscular dystrophy
Autosomal recessive MDs
Present at or soon after birth
About 50% due to deficiency of laminin-2
Others due to defective glycosylation of alpha-dystroglycans (impair binding to laminin) 
CK levels moderately high

Question 14

Bethlem Myopathy

Answer 14

Autosomal dominant
Onset before age 5
Proximal muscle weakness (mild to progressive)
Mutation affecting Type VI collagen (chromosome 21)

Question 15

Malignant hyperthermia

Answer 15

Rare complication of general anesthesia (1/100,000)
DMD, BMD, MMD patients particularly susceptible
Pathological release of Ca2+ in response to anesthesia (mutation in RYR gene, ryanodine receptor, protein in Ca2+ release channel)
Treated with dantrolene sodium (stabilizes membranes)

Question 16

Mutations in RYR1 gene

Answer 16

Altered Ca2+ release channel protein
Mutated channel opens more easily and stays open longer, thus flooding the cytosol with Ca2+
High intracellular levels of Ca2+ stimulate sustained muscle contraction (rigidity), high Ca2+ stimulates breakdown of glycogen, glycolysis and aerobic metabolism (resulting in excessive production of heat)