Neuromuscular disorders

Question 1

Dystrophinopathies

Answer 1

disorders caused by mutations in DMD, which encodes dystrophin
Progressive, symmetric
proximal > distal
Creatine kinase

Question 2

Severe vs mild dystrophinopathies

Answer 2

Skeletal: Duchenne and Becker
Cardiac: DMD-associated dilated cardiomyopathy

MILD: asymptomatic increase in CPK, may also have muscle cramps, myoglobinuria, and isolated quadriceps myopathy

Question 3

Duchenne muscular dystrophy

• onset
• progression

Answer 3

Onset before age 5
Wheelchair-bound by age 13
Cardiomyopathy by age 18
Lifespan ~ 24 years

Question 4

Duchenne muscular dystrophy symptoms

Answer 4

Delayed milestones
toe-walking and flat-footedness
Gait problems
Learning disabilities, resemble ADHD

Question 5

Becker Muscular dystrophy: clinical aspects

Answer 5

calf hypertrophy, activity induced cramping
Cardiac failure
There are some milder forms in which weakness manifests later

Mean survival: 5th decade

Question 6

DMD-associated dilated cardiomyopathy

Answer 6

risk for DCM and heart failure, no skeletal myopathy
Males present 2nd-3rd decade
Some females present later (heterozygous)
CK is elevated; some overlap with Becker

Question 7

Female carriers of DMD, BMD

Answer 7

30-50% of carriers are affected
2-10X normal CK concentration
most have no signs or symptoms, some have

Question 8

Mutational spectrum of DMD and BMD

Answer 8

deletions account for 60-70% of disease causing alleles in patients

duplications account for 5-10% of disease-causing alleles

Point mutations account for 25-35% of disease-causing alleles; missense mutations rare

Question 9

DMD genotype/phenotype

Answer 9

Out-of-frame deletions
Nonsense mutations
some missense and splicing mutations

No dystrophin produced

Question 10

BMD genotype/phenotype

Answer 10

In-frame deletions or duplications
Splicing and missense mutations
Non-truncating single-base changes that confers a protein product with intact N and C termini

some dystrophin produced; or normal amount with partial functionality

Question 11

DMD-associated DCM

Answer 11

mutations affect muscle promoter at exon 1 –> no dystrophin transcripts in cardiac muscle

Question 12

Carrier testing for dystrophinopathy when genotype is known vs not known

Answer 12

genotype known: test deletions and duplications using FISH, arrayCGH, MLPA. or do targeted sequence analysis

not known: linkage analysis with markers flanking DMD locus

Question 13

DMD/BMD management

Answer 13

physical therapy
developmental/educational evaluation
ECG/echocardiogram/cardiac MRI
Prednisone
Periperative care - malignant hyperthermia precautions
Pulmonary function testing

Question 14

Treatments for DMD

Answer 14

For dilated cardiomyopathy: Beta blocker, ACEi

Ataluren

Aminoglycosides

Question 15

Limb Girdle dystrophy

Answer 15

Predominatly involvles pelvic girdle and shoulder girdle; difficulty rising from chair and raising arms above head

16 genes implicated, 6 AD, 10 AR
CK elevated
Cardiac evaluation through ECG, echocardiogram
Muscle biopsy - immunohistostaining
DNA testing

Question 16

Emery Dreifus muscular dystrophy

Answer 16

Part of large group of “laminopathies”
X-linked (EMD) or AD (LMNA/C) or AR (LMNA)

Typically childhood onset
toe-walking, flexed elbows
Progressive weakness and wasting in distinctive humeroperoneal distribution

Question 17

Facioscapulohumeral muscular dystrophy

Answer 17

AD disorder caused by deletion of integral number of tandem repeats
High penetrance
weakness in facial muscles by age 20, dorsiflexors, scapular muscles

Hearing impairment, asymptomatic retinal vasculopathy
CK normal or mildly elevated

Question 18

Myotonic dystrophy inheritance

Answer 18

Most common AD disorder

Extreme variability, anticipation, differential expansion in maternal and paternal germlines

Question 19

Myotonic dystrophy physical signs

Answer 19

Myotonic facies: ptosis, mouth hangs open, atrophic and weak SCMs
Frontal balding
cataracts
Weak wrist extension
Myotonic contraction with tapping thenar eminence
Cannot quickly open clenched fist
Reflexes initially normal, but may become reduced or absent

Question 20

Myotonic dystorphy genetics

Answer 20

Expansion of CTG triplet in 3’ UTR of DMPK\causes toxic GOF of abnormally stored RNA, deregulated RNA binding proteins

Normal allele and premutation –> no clinical features
Protomutation (50-80 repeats) - asymptomatic or mild, late-onset
200-500 repeats - onset in 3rd or 4th decade
-1800 childhood onset
>1000 congenital myotonic dystrophy

Question 21

Myotonic dystrophy parent-of-origin effect

Answer 21

Full mutations more likely to expand when maternally inherited
Protomutations more likely to expand when paternally inherited

Question 22

Congenital myotonic dystrophy features

Answer 22

Polyhydramnios
Floppy at birth
Respiratory issues
Feeding issues
Facial diplegia with "tented" mouth
Mortality 20% in neonatal period
Most surviving children have significant learning disability
Some have milder phenotype and present later in infancy/early childhood

Question 23

Proximal myotonic myopathy (PROMM)

Answer 23

AD; may be clinically indistinguishable from myotonic dystrophy
Proximal weakness with mild myotonia

Question 24

Nemaline myopathy

Answer 24

Muscle weakness, but muscle fibers not dystrophic; have abnormal staining or protein aggregate
Many genetic causes

Question 25

Congenital myasthenic syndromes

Answer 25

Rare
Most are AR

Myasthenic:

• weakness or fatigue that gets worse with exertion
• can involved eye and facial muscles, swallowing, respiratory issues
• generally responds to anticholinesterase

Congenital:

• early-onset, genetic (later onset also possible)
• family history
• peculiar EMG pattern with repetitive response

Life-long, can improve or worsen
Treatment depends on genetic subtype

Question 26

Spinal muscular atrophy (all types)

Answer 26

AR
global hypotonia and paralysis
Anterior horn cell degeneration
Reduced tone, absent reflexes
CK normal; cognition normal

Question 27

SMA type 0

Answer 27

severe, prenatal onset

arthrogryposis and respiratory compromise at birth

Question 28

SMA type 1

Answer 28

onset before 6 months
weakness and hypotonia
never able to sit or walk
fatal respiratory failure typical by 2 years

Question 29

SMA types:

• 2
• 3
• 4

Answer 29

2 - onset within 1st year; sit, never walk
3 - (Kugelberg-Welander) - onset later in childhood, walk initially, survival to adulthood
4 - adult onset

Question 30

Congenital muscular dystrophies

Answer 30

Muscle weakness with dystrophic muscles on biopsy
Onset at birth or early infancy
Elevated CPK
Most with brain/CNS involvement
Most are AR

Question 31

Work-up for neuromuscular disorders

Answer 31

CPK-creatine phosphikinase
Echocardiogram, EKG
Pulmonary function
Electromyography
Nerve conduction study
MRI brain or spine
Muscle biopsy
DNA analysis

Question 32

Anesthesia concerns of neuromuscular disorders

Answer 32

Inhaled anesthetic agents - risk of rhabdomyolysis and malignant hyperthermia

other risks: prolonged weakness or paralysis, hyperkalemia, delirium