1. Myotonia Congenita Shannon L Venance, MD PhD ICNDM, Kansas City June 3, 2007

2. Disclosure Statement NIH: 8U54 NS059065 funding for the Consortium for Clinical Investigation of Neurological Channelopathies NIH: 8U54 NS059065 funding for the Consortium for Clinical Investigation of Neurological Channelopathies Port Elgin Rotarians for patient- centered Muscular Dystrophy Research Port Elgin Rotarians for patient- centered Muscular Dystrophy Research

3. Nondystrophic Myotonias disorders of muscle membrane excitability painless muscle stiffness

4. Caveats marked phenotypic variability within and between affected individuals and kindreds (e.g. Thomsen pedigree P480L ) 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 modifying genes and/or environmental factors yet to be determined need for prospectively collected, standardized data need for prospectively collected, standardized data

5. 27 yo male with muscle stiffness 27 yo male with muscle stiffness went to his family physician at age 12 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 “couldn’t keep up” in ? grade 1 but “tried to hide it by constantly moving” knew he “couldn’t keep up” in ? grade 1 but “tried to hide it by constantly moving” responds well to mexiletine responds well to mexiletine 2 sisters also affected, but to a lesser degree 2 sisters also affected, but to a lesser degree parents clinically and (dad electrophysiologically) unaffected parents clinically and (dad electrophysiologically) unaffected ocular myotonia; lid lag; percussion and grip myotonia - improves with repetition ocular myotonia; lid lag; percussion and grip myotonia - improves with repetition hypertrophy of thoracolumbar paraspinals, thigh and leg; mild restriction of ankle dorsiflexion hypertrophy of thoracolumbar paraspinals, thigh and leg; mild restriction of ankle dorsiflexion

6. 37 yo male with lifelong muscle stiffness (father similarly affected) 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 onset in infancy: stiffness noted with rolling over and crawling; frequent falls when learning to walk stiffness is painless and improves with activity 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” “worse in the cold” flecainide 100 mg bid helpful (tocainide was better) 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 delayed eye opening with forced eye closure, better with repetition; lid lag; mild percussion, grip (and widespread electrical) myotonia well-developed musculature well-developed musculature

7. MC: AR and AD typically onset in 1 st decade typically onset in 1 st decade painless muscle stiffness; mild to severe painless muscle stiffness; mild to severe “warm-up” “warm-up” may not be prominent if severe myotonia triggers incl activation after rest, stress/startle, pregnancy triggers incl activation after rest, stress/startle, pregnancyExam………. muscle hypertrophy (+/- atrophy) muscle hypertrophy (+/- atrophy) ocular, grip and percussion myotonia w/ warmup ocular, grip and percussion myotonia w/ warmup lid lag lid lag stair test stair test –10 stairs ~ 4 seconds if unaffected EDX – diffuse electrical myotonia

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

9. Lumpers vs. Splitters Big picture gal?Detail guy? Cl vs Na MC+v, PAM+v, PMC

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

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

12. inheritance Thomsen AD Becker AR PAM AD clinical myotonia mild-moderate face; UE > LE mod-severe LE > UE fluctuating to severe age of onset 1 st decade 1 st -2 nd decade childhood late 1 st decade triggersrestrest exercise, K warm-upimprovesimproves? cold no effect not really episodic weakness no ± transient proximal no lid lag yesyesyes hypertrophy hypertrophymildmod ARM and MP treatmentmexiletineflecanidemexiletineflecanidemexiletineacetazolamide geneCLCN1CLCN1SCN4A

13. Questions to be answered Will the differences in clinical phenotype combined with EDX studies accurately predict genotype? 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? 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? Will treatment prevent the permanent weakness seen in a proportion of NDM patients? How do we identify those that will benefit from treatment?

14. 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

15. AR myotonia congenita (Becker) ~ 1/50,000 onset late in 1 st 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 ↑

16. AD myotonia congenita (Thomsen) ~1/15,000-25,000 ~1/15,000-25,000 onset in infancy or early childhood onset in infancy or early childhood face, tongue, pharyngeal muscles, hands and legs face, tongue, pharyngeal muscles, hands and legs triggered by activation after rest, startle, stress, increased in pregnancy triggered by activation after rest, startle, stress, increased in pregnancy “warm-up” will minimize stiffness “warm-up” will minimize stiffness muscle hypertrophy without weakness muscle hypertrophy without weakness grip and percussion myotonia; lid lag and ocular myotonia grip and percussion myotonia; lid lag and ocular myotonia CK normal or mildly increased CK normal or mildly increased

17. Fournier et al, 2006 Electrophysiology Helps routine NCS ( ± after potentials) routine NCS ( ± after potentials) EMG: myotonic potentials EMG: myotonic potentials short exercise protocol with repetition ± cold exposure short exercise protocol with repetition ± cold exposure more in the afternoon Neurophysiology session!!