Myotonia CongenitaMyotonia Congenita

Shannon L Venance, MD PhDShannon L Venance, MD PhD

ICNDM, Kansas CityICNDM, Kansas City

June 3, 2007June 3, 2007

Disclosure StatementDisclosure Statement

NIH: 8U54 NS059065 funding for NIH: 8U54 NS059065 funding for the Consortium for Clinical the Consortium for Clinical Investigation of Neurological Investigation of Neurological ChannelopathiesChannelopathies

Port Elgin Rotarians for patient-Port Elgin Rotarians for patient-centered Muscular Dystrophy centered Muscular Dystrophy ResearchResearch

Nondystrophic Nondystrophic MyotoniasMyotonias

disorders of muscle membrane excitabilitydisorders of muscle membrane excitabilitypainless muscle stiffnesspainless muscle stiffness

chloride channelopathies (chloride channelopathies (CLCN1CLCN1) ) – myotonia congenita (MC)myotonia congenita (MC)

autosomal dominant (Thomsen) 1876autosomal dominant (Thomsen) 1876 autosomal recessive (Becker) 1977autosomal recessive (Becker) 1977

– myotonic dystrophy type 1 and 2myotonic dystrophy type 1 and 2

sodium channelopathies (sodium channelopathies (SCN4ASCN4A))– paramyotonia congenita (PMC)paramyotonia congenita (PMC)– potassium-aggravated myotonia (PAM)potassium-aggravated myotonia (PAM)

AZM-responsive myotoniaAZM-responsive myotonia myotonia fluctuans and myotonia permanensmyotonia fluctuans and myotonia permanens

– hyperkalemic periodic paralysis (HyperPP)hyperkalemic periodic paralysis (HyperPP)

CaveatsCaveats

marked phenotypic variability within and marked phenotypic variability within and between affected individuals and between affected individuals and kindreds kindreds (e.g. Thomsen pedigree P480L )(e.g. Thomsen pedigree P480L )– dominant mutations with dominant mutations with reduced reduced

penetrancepenetrance– asymptomatic heterozygotes in AD pedigreesasymptomatic heterozygotes in AD pedigrees– identical mutations in dominant and identical mutations in dominant and

recessive pedigreesrecessive pedigrees– kindreds with unusual featureskindreds with unusual features

modifying genes and/or environmental modifying genes and/or environmental factors yet to be determinedfactors yet to be determined

need for prospectively collected, need for prospectively collected, standardized data standardized data

27 yo male with muscle stiffness27 yo male with muscle stiffness went to his family physician at age 12went to his family physician at age 12

– parents and teachers were “hassling” him to “try parents and teachers were “hassling” him to “try harder”harder”

– ““last kid off the mark in gym class”last kid off the mark in gym class” knew he “couldn’t keep up” in ? grade 1 but knew he “couldn’t keep up” in ? grade 1 but

“tried to hide it by constantly moving”“tried to hide it by constantly moving” responds well to mexiletineresponds well to mexiletine 2 sisters also affected, but to a lesser degree2 sisters also affected, but to a lesser degree parents clinically and (dad parents clinically and (dad

electrophysiologically) unaffectedelectrophysiologically) unaffected ocular myotonia; lid lag; percussion and grip ocular myotonia; lid lag; percussion and grip

myotonia - improves with repetitionmyotonia - improves with repetition hypertrophy of thoracolumbar paraspinals, hypertrophy of thoracolumbar paraspinals,

thigh and leg; mild restriction of ankle thigh and leg; mild restriction of ankle dorsiflexiondorsiflexion

37 yo male with lifelong muscle stiffness 37 yo male with lifelong muscle stiffness (father similarly affected)(father similarly affected)

onset in infancy: stiffness noted with rolling onset in infancy: stiffness noted with rolling over and crawling; frequent falls when over and crawling; frequent falls when learning to walk learning to walk

stiffness is painless and improves with stiffness is painless and improves with activityactivity– stopped playing hockey as a teenager – fell on the stopped playing hockey as a teenager – fell on the

ice, unable to “jump over the boards”ice, unable to “jump over the boards”– continues to golf and play tennis – uses continual continues to golf and play tennis – uses continual

motion to stay loosemotion to stay loose ““worse in the cold”worse in the cold” flecainide 100 mg bid helpful (tocainide was flecainide 100 mg bid helpful (tocainide was

better)better) delayed eye opening with forced eye closure, delayed eye opening with forced eye closure,

better with repetition; lid lag; mild percussion, better with repetition; lid lag; mild percussion, grip (and widespread electrical) myotoniagrip (and widespread electrical) myotonia

well-developed musculature well-developed musculature

MC: AR MC: AR andand AD AD

typically onset in 1typically onset in 1stst decade decade painless muscle stiffness; mild to severepainless muscle stiffness; mild to severe ““warm-up”warm-up”

may not be prominent if severe myotoniamay not be prominent if severe myotonia triggers incl activation after rest, triggers incl activation after rest,

stress/startle, pregnancystress/startle, pregnancyExam……….Exam………. muscle hypertrophy (+/- atrophy)muscle hypertrophy (+/- atrophy) ocular, grip and percussion myotonia w/ ocular, grip and percussion myotonia w/

warmupwarmup lid laglid lag stair test stair test

– 10 stairs ~ 4 seconds if unaffected10 stairs ~ 4 seconds if unaffected

EDX – diffuse electrical myotoniaEDX – diffuse electrical myotonia

AR (AR (vs.vs. AD) AD)

absent family historyabsent family history older onset older onset more severely affected ; 15-20% painfulmore severely affected ; 15-20% painful leg onset (vs. face/hands in AD)leg onset (vs. face/hands in AD) males males ±± more severely affected than females more severely affected than females transient weakness transient weakness ±± progressive into 4 progressive into 4thth decade decade ±± focal atrophy (distal forearms and neck) focal atrophy (distal forearms and neck) a proportion develop fixed weaknessa proportion develop fixed weakness

Lumpers vs. SplittersLumpers vs. Splitters

Big picture gal? Detail guy?

Cl vs Na MC+v, PAM+v, PMC

Myotonia Congenita Myotonia Congenita VariantsVariants

due to due to CLCN1CLCN1; dominant inheritance; dominant inheritance– myotonia levior myotonia levior

milder, later onset, grip stiffness after rest milder, later onset, grip stiffness after rest no hypertrophyno hypertrophy

– fluctuating myotonia congenita fluctuating myotonia congenita (G200R)(G200R) painfulpainful; legs > arms; legs > arms percussion and grip myotoniapercussion and grip myotonia fluctuates with fluctuates with symptom free intervalssymptom free intervals stiffness with activation after rest, pregnancy, stiffness with activation after rest, pregnancy,

fasting, stressfasting, stress

and…Potassium and…Potassium Aggravated Myotonia Aggravated Myotonia

(PAM)(PAM) sodium channelopathies (sodium channelopathies (SCN4A); SCN4A); often ADoften AD

– potassium potassium and and exerciseexercise trigger symptoms trigger symptoms– do not worsen after cold exposuredo not worsen after cold exposure– do not have episodic weaknessdo not have episodic weakness

myotonia fluctuansmyotonia fluctuans– asymptomatic periodsasymptomatic periods; worsening myotonia with delay ; worsening myotonia with delay

after start of exercise; ocular paramyotoniaafter start of exercise; ocular paramyotonia acetazolamide responsive myotoniaacetazolamide responsive myotonia

– painfulpainful; may worsen throughout childhood and ; may worsen throughout childhood and adolescence with dramatic improvement with adolescence with dramatic improvement with ACZACZ

myotonia permanensmyotonia permanens (G1306E) sporadic (G1306E) sporadic– severe, persistent myotonia of face, limbs and severe, persistent myotonia of face, limbs and

intercostals; hypertrophy of neck and shoulder muscles; intercostals; hypertrophy of neck and shoulder muscles; ± ± respiratory compromiserespiratory compromise

inheritanceinheritance Thomsen ADThomsen AD Becker ARBecker AR PAM ADPAM AD PMC ADPMC AD

clinical clinical myotoniamyotonia

mild-mild-moderatemoderate

face; UE > face; UE > LELE

mod-severemod-severe

LE > UELE > UEfluctuating to fluctuating to

severeseveremild-modmild-mod

face, UE, LEface, UE, LE

age of age of onsetonset

11stst decade decade 11stst -2 -2ndnd decadedecade

childhoodchildhood

late 1late 1stst decadedecade

late 1late 1stst decade decade

triggerstriggers restrest restrest exercise, Kexercise, K exercise, coldexercise, cold

warm-upwarm-up improvesimproves improvesimproves ?? worsensworsens

coldcold no effectno effect no effectno effect not reallynot really myotonia myotonia worse; ± worse; ± paralysisparalysis

episodic episodic weaknessweakness

nono ± transient ± transient proximalproximal

nono yesyes

lid laglid lag yesyes yesyes yesyes yesyes

hypertrophhypertroph

yy

mildmild modmod ARM and MPARM and MP ±±

treatmenttreatment mexiletinemexiletine

flecanideflecanidemexiletinemexiletine

flecanideflecanidemexiletinemexiletine

acetazolamidacetazolamidee

mexiletinemexiletine

acetazolamideacetazolamide

genegene CLCN1CLCN1 CLCN1CLCN1 SCN4ASCN4A SCN4ASCN4A

Questions to be Questions to be answeredanswered

Will the differences in clinical Will the differences in clinical phenotype combined with EDX studies phenotype combined with EDX studies accurately predict genotype?accurately predict genotype?

What additional genetic and/or What additional genetic and/or environmental factors are responsible environmental factors are responsible for the intra- and inter-familial for the intra- and inter-familial phenotypic variability?phenotypic variability?

Will treatment prevent the permanent Will treatment prevent the permanent weakness seen in a proportion of NDM weakness seen in a proportion of NDM patients? How do we identify those patients? How do we identify those that will benefit from treatment?that will benefit from treatment?

AcknowledgementsAcknowledgements

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

AR myotonia congenitaAR myotonia congenita(Becker)(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 ↑

AD myotonia congenitaAD myotonia congenita(Thomsen)(Thomsen)

~1/15,000-25,000~1/15,000-25,000 onset in onset in infancy or early childhoodinfancy or early childhood face, tongue, pharyngeal muscles, handsface, tongue, pharyngeal muscles, hands

and legsand legs triggered by activation after rest, startle, triggered by activation after rest, startle,

stress, increased in pregnancystress, increased in pregnancy ““warm-up” will minimize stiffnesswarm-up” will minimize stiffness muscle hypertrophy without weaknessmuscle hypertrophy without weakness grip and percussion myotonia; lid lag and grip and percussion myotonia; lid lag and

ocular myotoniaocular myotonia CK normal or mildly increasedCK normal or mildly increased

Fournier et al, 2006

Electrophysiology Electrophysiology HelpsHelps

routine NCS (routine NCS (± after potentials)± after potentials) EMG: myotonic potentialsEMG: myotonic potentials short exercise protocol with short exercise protocol with

repetition repetition ±± cold exposure cold exposure

more in the afternoon Neurophysiology session!!