Neuromuscular disorders Flashcards
Dystrophinopathies
disorders caused by mutations in DMD, which encodes dystrophin
Progressive, symmetric
proximal > distal
Creatine kinase
Severe vs mild dystrophinopathies
Skeletal: Duchenne and Becker
Cardiac: DMD-associated dilated cardiomyopathy
MILD: asymptomatic increase in CPK, may also have muscle cramps, myoglobinuria, and isolated quadriceps myopathy
Duchenne muscular dystrophy
- onset
- progression
Onset before age 5
Wheelchair-bound by age 13
Cardiomyopathy by age 18
Lifespan ~ 24 years
Duchenne muscular dystrophy symptoms
Delayed milestones
toe-walking and flat-footedness
Gait problems
Learning disabilities, resemble ADHD
Becker Muscular dystrophy: clinical aspects
calf hypertrophy, activity induced cramping
Cardiac failure
There are some milder forms in which weakness manifests later
Mean survival: 5th decade
DMD-associated dilated cardiomyopathy
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
Female carriers of DMD, BMD
30-50% of carriers are affected
2-10X normal CK concentration
most have no signs or symptoms, some have
Mutational spectrum of DMD and BMD
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
DMD genotype/phenotype
Out-of-frame deletions
Nonsense mutations
some missense and splicing mutations
No dystrophin produced
BMD genotype/phenotype
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
DMD-associated DCM
mutations affect muscle promoter at exon 1 –> no dystrophin transcripts in cardiac muscle
Carrier testing for dystrophinopathy when genotype is known vs not known
genotype known: test deletions and duplications using FISH, arrayCGH, MLPA. or do targeted sequence analysis
not known: linkage analysis with markers flanking DMD locus
DMD/BMD management
physical therapy developmental/educational evaluation ECG/echocardiogram/cardiac MRI Prednisone Periperative care - malignant hyperthermia precautions Pulmonary function testing
Treatments for DMD
For dilated cardiomyopathy: Beta blocker, ACEi
Ataluren
Aminoglycosides
Limb Girdle dystrophy
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
Emery Dreifus muscular dystrophy
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
Facioscapulohumeral muscular dystrophy
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
Myotonic dystrophy inheritance
Most common AD disorder
Extreme variability, anticipation, differential expansion in maternal and paternal germlines
Myotonic dystrophy physical signs
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
Myotonic dystorphy genetics
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
Myotonic dystrophy parent-of-origin effect
Full mutations more likely to expand when maternally inherited
Protomutations more likely to expand when paternally inherited
Congenital myotonic dystrophy features
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
Proximal myotonic myopathy (PROMM)
AD; may be clinically indistinguishable from myotonic dystrophy
Proximal weakness with mild myotonia
Nemaline myopathy
Muscle weakness, but muscle fibers not dystrophic; have abnormal staining or protein aggregate
Many genetic causes
