Transcript Myotonia Congenita

Myotonia Congenita
Shannon L Venance, MD PhD
ICNDM, Kansas City
June 3, 2007
Disclosure Statement
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NIH: 8U54 NS059065 funding for the
Consortium for Clinical Investigation of
Neurological Channelopathies
Port Elgin Rotarians for patientcentered Muscular Dystrophy Research
Nondystrophic Myotonias
disorders of muscle membrane excitability
painless muscle stiffness
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chloride channelopathies (CLCN1)
– myotonia congenita (MC)
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autosomal dominant (Thomsen) 1876
autosomal recessive (Becker) 1977
– myotonic dystrophy type 1 and 2
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sodium channelopathies (SCN4A)
– paramyotonia congenita (PMC)
– potassium-aggravated myotonia (PAM)
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AZM-responsive myotonia
myotonia fluctuans and myotonia permanens
– hyperkalemic periodic paralysis (HyperPP)
Caveats
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marked phenotypic variability within and
between affected individuals and kindreds
(e.g. Thomsen pedigree P480L )
– dominant mutations with reduced penetrance
– asymptomatic heterozygotes in AD pedigrees
– identical mutations in dominant and recessive
pedigrees
– kindreds with unusual features
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modifying genes and/or environmental factors
yet to be determined
need for prospectively collected, standardized
data
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27 yo male with muscle stiffness
went to his family physician at age 12
– parents and teachers were “hassling” him to “try harder”
– “last kid off the mark in gym class”
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knew he “couldn’t keep up” in ? grade 1 but “tried
to hide it by constantly moving”
responds well to mexiletine
2 sisters also affected, but to a lesser degree
parents clinically and (dad electrophysiologically)
unaffected
ocular myotonia; lid lag; percussion and grip
myotonia - improves with repetition
hypertrophy of thoracolumbar paraspinals, thigh
and leg; mild restriction of ankle dorsiflexion
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37 yo male with lifelong muscle stiffness (father
similarly affected)
onset in infancy: stiffness noted with rolling over
and crawling; frequent falls when learning to walk
stiffness is painless and improves with activity
– stopped playing hockey as a teenager – fell on the ice,
unable to “jump over the boards”
– continues to golf and play tennis – uses continual
motion to stay loose
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“worse in the cold”
flecainide 100 mg bid helpful (tocainide was
better)
delayed eye opening with forced eye closure,
better with repetition; lid lag; mild percussion, grip
(and widespread electrical) myotonia
well-developed musculature
MC: AR and AD
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typically onset in 1st decade
painless muscle stiffness; mild to severe
“warm-up”
may not be prominent if severe myotonia
triggers incl activation after rest, stress/startle,
pregnancy
Exam……….
 muscle hypertrophy (+/- atrophy)
 ocular, grip and percussion myotonia w/ warmup
 lid lag
 stair test
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– 10 stairs ~ 4 seconds if unaffected
EDX – diffuse electrical myotonia
AR (vs. AD)
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absent family history
older onset
more severely affected ; 15-20% painful
leg onset (vs. face/hands in AD)
males ± more severely affected than females
transient weakness
± progressive into 4th decade
± focal atrophy (distal forearms and neck)
a proportion develop fixed weakness
Lumpers vs. Splitters
Cl vs Na
Big picture gal?
MC+v, PAM+v, PMC
Detail guy?
Myotonia Congenita
Variants
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due to CLCN1; dominant inheritance
– myotonia levior
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milder, later onset, grip stiffness after rest
no hypertrophy
– fluctuating myotonia congenita (G200R)
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painful; legs > arms
percussion and grip myotonia
fluctuates with symptom free intervals
stiffness with activation after rest, pregnancy, fasting,
stress
and…Potassium Aggravated
Myotonia (PAM)
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sodium channelopathies (SCN4A); often AD
– potassium and exercise trigger symptoms
– do not worsen after cold exposure
– do not have episodic weakness
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myotonia fluctuans
– asymptomatic periods; worsening myotonia with delay after
start of exercise; ocular paramyotonia
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acetazolamide responsive myotonia
– painful; may worsen throughout childhood and adolescence
with dramatic improvement with ACZ
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myotonia permanens (G1306E) sporadic
– severe, persistent myotonia of face, limbs and intercostals;
hypertrophy of neck and shoulder muscles; ± respiratory
compromise
inheritance
Thomsen AD
Becker AR
PAM AD
PMC AD
clinical
myotonia
mild-moderate
face; UE > LE
mod-severe
LE > UE
fluctuating to
severe
mild-mod
face, UE, LE
age of onset
1st decade
1st -2nd decade
childhood
late 1st decade
late 1st decade
triggers
rest
rest
exercise, K
exercise, cold
warm-up
improves
improves
?
worsens
cold
no effect
no effect
not really
myotonia worse;
± paralysis
episodic
weakness
no
± transient
proximal
no
yes
lid lag
yes
yes
yes
yes
hypertrophy
mild
mod
ARM and MP
±
treatment
mexiletine
flecanide
mexiletine
flecanide
mexiletine
acetazolamide
mexiletine
acetazolamide
gene
CLCN1
CLCN1
SCN4A
SCN4A
Questions to be answered
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Will the differences in clinical phenotype
combined with EDX studies accurately
predict genotype?
What additional genetic and/or
environmental factors are responsible for
the intra- and inter-familial phenotypic
variability?
Will treatment prevent the permanent
weakness seen in a proportion of NDM
patients? How do we identify those that will
benefit from treatment?
Acknowledgements
London ON CINCH team
CINCH
Angelika Hahn
Rochester NY
Wilma Koopman
Robert Griggs
Kori LaDonna
Rabi Tawil
Karen Findlater
Barbara Herr
Kansas City, KS
Rick Barohn
Laura Herbelin
AR myotonia congenita
(Becker)
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~ 1/50,000
onset late in 1st decade; more severe than AD
legs > arms; 15% painful
warm-up helpful for most, but not all
triggered after rest, stress, worsens during pregnancy
grip, neck > tongue myotonia; lid lag ~50%
hypertrophy often of gluteal and leg muscles with
atrophy of forearm muscles
transient weakness but % will develop permanent
weakness
± wrist and ankle contractures; toe walking
CK normal to 2-3x ↑
AD myotonia congenita
(Thomsen)
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~1/15,000-25,000
onset in infancy or early childhood
face, tongue, pharyngeal muscles, hands and
legs
triggered by activation after rest, startle, stress,
increased in pregnancy
“warm-up” will minimize stiffness
muscle hypertrophy without weakness
grip and percussion myotonia; lid lag and ocular
myotonia
CK normal or mildly increased
Electrophysiology Helps
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routine NCS (± after potentials)
EMG: myotonic potentials
short exercise protocol with repetition
± cold exposure
Fournier et al, 2006
more in the afternoon Neurophysiology session!!