Myotonia Congenita

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Myotonia Congenita

• Shannon L Venance, MD PhD
• ICNDM, Kansas City
• June 3, 2007

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Disclosure Statement

• NIH 8U54 NS059065 funding for the Consortium for
  Clinical Investigation of Neurological
  Channelopathies
• Port Elgin Rotarians for patient-centered
  Muscular Dystrophy Research

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Nondystrophic Myotoniasdisorders of muscle
membrane excitabilitypainless muscle stiffness

• chloride channelopathies (CLCN1)
• myotonia congenita (MC)
• autosomal dominant (Thomsen) 1876
• autosomal recessive (Becker) 1977
• myotonic dystrophy type 1 and 2
• sodium channelopathies (SCN4A)
• paramyotonia congenita (PMC)
• potassium-aggravated myotonia (PAM)
• AZM-responsive myotonia
• myotonia fluctuans and myotonia permanens
• hyperkalemic periodic paralysis (HyperPP)

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Caveats

• 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
• 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
• knew he couldnt 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
• 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

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MC AR and AD

• 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
• 10 stairs 4 seconds if unaffected
• EDX diffuse electrical myotonia

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AR (vs. AD)

• 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

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Lumpers vs. Splitters
Cl vs Na
MCv, PAMv, PMC
Big picture gal?
Detail guy?
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Myotonia Congenita Variants

• due to CLCN1 dominant inheritance
• myotonia levior
• milder, later onset, grip stiffness after rest
• no hypertrophy
• fluctuating myotonia congenita (G200R)
• painful legs arms
• percussion and grip myotonia
• fluctuates with symptom free intervals
• stiffness with activation after rest, pregnancy,
  fasting, stress

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andPotassium Aggravated Myotonia (PAM)

• sodium channelopathies (SCN4A) often AD
• potassium and exercise trigger symptoms
• do not worsen after cold exposure
• do not have episodic weakness
• myotonia fluctuans
• asymptomatic periods worsening myotonia with
  delay after start of exercise ocular
  paramyotonia
• acetazolamide responsive myotonia
• painful may worsen throughout childhood and
  adolescence with dramatic improvement with ACZ
• myotonia permanens (G1306E) sporadic
• severe, persistent myotonia of face, limbs and
  intercostals hypertrophy of neck and shoulder
  muscles respiratory compromise

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Questions to be answered

• 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?

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Acknowledgements
London ON CINCH team Angelika Hahn Wilma
Koopman Kori LaDonna Karen Findlater
CINCH Rochester NY Robert Griggs Rabi
Tawil Barbara Herr Kansas City, KS Rick
Barohn Laura Herbelin
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AR myotonia congenita(Becker)

• 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 ?

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AD myotonia congenita(Thomsen)

• 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

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Electrophysiology Helps

• routine NCS ( after potentials)
• EMG myotonic potentials
• short exercise protocol with repetition cold
  exposure

Fournier et al, 2006
more in the afternoon Neurophysiology session!!