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Exercise Testing in Channelopathies. Indications Periodic Paralysis Periodic Paralysis Myotonic Disorders Myotonic Disorders –Dystrophic –Nondystrophic.

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Presentation on theme: "Exercise Testing in Channelopathies. Indications Periodic Paralysis Periodic Paralysis Myotonic Disorders Myotonic Disorders –Dystrophic –Nondystrophic."— Presentation transcript:

1 Exercise Testing in Channelopathies

2 Indications Periodic Paralysis Periodic Paralysis Myotonic Disorders Myotonic Disorders –Dystrophic –Nondystrophic –Paramyotonia Neuromuscular junction Disorders Neuromuscular junction Disorders –Myasthenia gravis –Eaton-Lambert –Botulism –Congenital myasthenic syndromes

3 Scientific Background Resting State Resting membrane potential -85mV Resting membrane potential -85mV Na+ and Ca+ concentrations higher extracellularly than intracellularly Na+ and Ca+ concentrations higher extracellularly than intracellularly K+ and Cl- concentrations higher intracellularly than extracellularly K+ and Cl- concentrations higher intracellularly than extracellularly Constant balance between high intracellular K+ and low intracellular Na+ by active transport through specific ion channels Constant balance between high intracellular K+ and low intracellular Na+ by active transport through specific ion channels

4 Scientific Background Ion Channels Ion specific channels are macromolecular proteins spanning lipid bilayer of cells and can be opened or closed. Ion specific channels are macromolecular proteins spanning lipid bilayer of cells and can be opened or closed. Ions can flow through open channels Ions can flow through open channels Flow depends on: Electrochemical gradient Flow depends on: Electrochemical gradient Relative permeability Relative permeability Relative selectivity of the channel Relative selectivity of the channel Voltage depend gating: gating is mediated by channels sensitivity to electrical potential changes of the membrane. Voltage depend gating: gating is mediated by channels sensitivity to electrical potential changes of the membrane. Other channel types: some do not require a change in voltage to open or close e.g. ligand gated channels, exchangers, transporters etc Other channel types: some do not require a change in voltage to open or close e.g. ligand gated channels, exchangers, transporters etc

5 Scientific Background Depolarization Threshold is reached. Threshold is reached. Voltage gated Na channels activated, leading to increased Na conductance and thus fast Na influx into cell. Voltage gated Na channels activated, leading to increased Na conductance and thus fast Na influx into cell.

6 Scientific Background Repolarization With change in polarity, inactivation of Na channel occurs, K and Cl conductance rises With change in polarity, inactivation of Na channel occurs, K and Cl conductance rises Therefore, K out and Cl in, reestablishing negative resting membrane potential. Therefore, K out and Cl in, reestablishing negative resting membrane potential.

7 Model for membrane excitability disorders Membrane excitability is a balance between excitation and inhibition. Membrane excitability is a balance between excitation and inhibition.

8 Model for membrane excitability disorders Excitatory influences (e x ) Inhibitory influences (i y ) Glutamate receptors Na channels Ca channels GABA receptors K channels Cl channels E= (e1+e2+e3)- (i1+i2+i3)

9 Model for membrane excitability disorders Physiological effects of SCN4A and ClCN1 mutations e.g. hyperkalemic periodic paralysis, paramyotonia congenita, Myotonia congenita. Physiological effects of SCN4A and ClCN1 mutations e.g. hyperkalemic periodic paralysis, paramyotonia congenita, Myotonia congenita.

10 Diseases of Ion Channels Ion channels found in: muscle: periodic paralysis, myotonia muscle: periodic paralysis, myotonia brain: epilepsy, familial hemiplegic migraine, episodic ataxia brain: epilepsy, familial hemiplegic migraine, episodic ataxia heart: long QT syndrome, Andersen-Tawil syndrome heart: long QT syndrome, Andersen-Tawil syndrome

11 Protocol for Evaluation of Myotonia & Periodic Paralysis 1. Routine motor & sensory nerve conduction studies in upper & lower limbs. 1. Routine motor & sensory nerve conduction studies in upper & lower limbs. 2. EMG: include distal, proximal, facial and paraspinal muscles. 2. EMG: include distal, proximal, facial and paraspinal muscles. 3. Muscle cooling if suspicion of paramyotonia congenita. 3. Muscle cooling if suspicion of paramyotonia congenita. a. Wrap arm in plastic bag, immerse in ice water for min till skin temperature is 20°C. Remove hand if weakness develops. a. Wrap arm in plastic bag, immerse in ice water for min till skin temperature is 20°C. Remove hand if weakness develops. b. EMG hand muscle. b. EMG hand muscle. c. Allow muscle to rewarm to precooling temp & continue to record EMG (may take >1 hour) c. Allow muscle to rewarm to precooling temp & continue to record EMG (may take >1 hour) 4. Short exercise test if above test does not yield definitive result. 4. Short exercise test if above test does not yield definitive result. a. Immobilize hand. Record ADM CMAP (Make sure immobilize hand). a. Immobilize hand. Record ADM CMAP (Make sure immobilize hand). b. Record CMAP every minute for 5 minutes with muscle at rest to ensure stable baseline. b. Record CMAP every minute for 5 minutes with muscle at rest to ensure stable baseline. c Perform max voluntary contraction for 10 sc. c Perform max voluntary contraction for 10 sc. d. Record CMAP immediately. If a decrement in CMAP is seen, continue to record CMAP every 10 seconds till returns to baseline (usually 1-2 mins). d. Record CMAP immediately. If a decrement in CMAP is seen, continue to record CMAP every 10 seconds till returns to baseline (usually 1-2 mins). e. In cases where decrement is seen after exercise, repeat same procedure several times to see if reduction in CMAP continues or habituates. e. In cases where decrement is seen after exercise, repeat same procedure several times to see if reduction in CMAP continues or habituates.

12 Protocol for Evaluation of Myotonia & Periodic Paralysis 5. Prolonged exercise test if above do not provide diagnostic clues. 5. Prolonged exercise test if above do not provide diagnostic clues. a. Immobilize hand. Record ADM CMAP (Make sure immobilize hand). a. Immobilize hand. Record ADM CMAP (Make sure immobilize hand). b. Record CMAP every minute for 5 minutes with muscle at rest to ensure stable baseline. b. Record CMAP every minute for 5 minutes with muscle at rest to ensure stable baseline. c. Perform max voluntary contraction for 5 minutes: resting every 15 sec for 3 seconds. c. Perform max voluntary contraction for 5 minutes: resting every 15 sec for 3 seconds. d. Ask patient to relax completely. d. Ask patient to relax completely. e. Record CMAP immediately, then every 2 minutes for 60 minutes afterwards or until there is no further decline (maybe >1 hour). e. Record CMAP immediately, then every 2 minutes for 60 minutes afterwards or until there is no further decline (maybe >1 hour). Decrement = (highest CMAP postexercise - smallest CMAP postexercise)/(highest CMAP postexercise) X 100. Decrement = (highest CMAP postexercise - smallest CMAP postexercise)/(highest CMAP postexercise) X 100. Any decrement >40% is abnormal. Any decrement >40% is abnormal. f. NB: Immediately after exercise, CMAP maybe larger before slow decline in amplitude. f. NB: Immediately after exercise, CMAP maybe larger before slow decline in amplitude. Comments: Comments: CMAP often increases with cooling in NORMAL individuals. CMAP often increases with cooling in NORMAL individuals. 1. Myotonia congenita may have an initial but transient decrement after exercise that quickly resolves. Not worsened by cooling, and, as in normality, may increase with cooling. 1. Myotonia congenita may have an initial but transient decrement after exercise that quickly resolves. Not worsened by cooling, and, as in normality, may increase with cooling. 2. Paramyotonia congenita have a prolonged decrement with combination of exercise and cooling that is still often apparent on rewarming. 2. Paramyotonia congenita have a prolonged decrement with combination of exercise and cooling that is still often apparent on rewarming.

13 Calculations Specificity = 97.8% Increment (highest CMAP postexercise – CMAP before exercise) X 100 / (CMAP before exercise) Any increment > 30% is abnormal for CMAP. Any increment > 25% is abnormal for CMAP area. Decrement (highest CMAP postexercise – smallest CMAP postexercise) X 100 / (CMAP postexercise) Any decrement > 40% is abnormal for CMAP. Any decrement > 45% is abnormal for CMAP area.

14 Common Channel Diseases

15 Electrophysiologic Testing

16 Electrophysiologic Testing in Channelopathies (Part 2)

17 Sensitivity / Specificity Mean sensitivity 63% Mean sensitivity 63% Primary periodic paralysis 81% Primary periodic paralysis 81% Chloride channelopathies 17% Chloride channelopathies 17% Thyrotoxic periodic paralysis 75% Thyrotoxic periodic paralysis 75% Specificity = 97.8% Specificity = 97.8%

18 Hypokalemic Periodic Paralysis: Exercise Test

19 Exercise Test: Amplitude increase

20 Exercise Test: Amplitude decrease

21 Myotonic dystrophy AD, trinucleotide (CTG) disorder on Chr 19q affecting myotonin gene. AD, trinucleotide (CTG) disorder on Chr 19q affecting myotonin gene. Usually present in late teens with distal weakness and delayed relaxation (milkmaid grip, percussion Myotonia) Usually present in late teens with distal weakness and delayed relaxation (milkmaid grip, percussion Myotonia) Stiffness that improves with repeated contractions. Stiffness that improves with repeated contractions. Classical appearance of bifacial weakness, temporal weakness (triangular facies), frontal balding, ptosis, neck flexor weakness, distal muscle wasting and weakness. Classical appearance of bifacial weakness, temporal weakness (triangular facies), frontal balding, ptosis, neck flexor weakness, distal muscle wasting and weakness. Other clinical features include: Other clinical features include: Cataracts (posterior capsule, multicolor pattern)) Cataracts (posterior capsule, multicolor pattern)) Cardiac conduction abnormalities Cardiac conduction abnormalities Pulmonary defects (pectus excavatum) Pulmonary defects (pectus excavatum) Endocrine dysfunction (diabetes, testicular atrophy, hypogonadism) Endocrine dysfunction (diabetes, testicular atrophy, hypogonadism) Hypersomina (sleep apnea syndrome) Hypersomina (sleep apnea syndrome) Mild cognitive impairment Mild cognitive impairment CK: mild to moderate elevation CK: mild to moderate elevation Muscle biopsy: atrophy Type I fibres, increase in central nucleation, ring fibres, occasional small angulated fibres. Muscle biopsy: atrophy Type I fibres, increase in central nucleation, ring fibres, occasional small angulated fibres. 10% congenital 10% congenital Anticipation more profound when inherited from mother Anticipation more profound when inherited from mother

22 Myotonic dystrophy A three-generation family affected with myotonic dystrophy. The degree of severity increases in each generation. The grandmother (right) is only slightly affected, but the mother (left) has a characteristic narrow face and somewhat limited facial expression. The baby is more severely affected and has the facial features of children with neonatal-onset myotonic dystrophy, including an open, triangular-shaped mouth. The infant has more than 1000 copies of the trinucleotide repeat, whereas the mother and grandmother each have approximately 100 repeats.

23 Myotonic dystrophy Electrophysiology Low CMAP maybe secondary to myopathy. Low CMAP maybe secondary to myopathy. Myotonia most prominent in distal hand, forearm extensor, tibialis anterior, facial muscle but not usually found in proximal muscles. Myotonia most prominent in distal hand, forearm extensor, tibialis anterior, facial muscle but not usually found in proximal muscles. MUAP analysis difficult if profound myotonia. MUAP analysis difficult if profound myotonia. Muscle cooling ahs no effect. Muscle cooling ahs no effect. Short exercise test produces drop in CMAP immediately after exercise. If CMAP recorded every 10 sec up to 2 min, it recovers to baseline. If short exercise test repeated, the decremental responses habituates. Short exercise test produces drop in CMAP immediately after exercise. If CMAP recorded every 10 sec up to 2 min, it recovers to baseline. If short exercise test repeated, the decremental responses habituates.

24 Proximal Myotonic Myopathy AD, trinucleotide (CCTG) disorder on Chr 3q AD, trinucleotide (CCTG) disorder on Chr 3q Weakness is mostly proximal and may have muscle hypertrophy. Weakness is mostly proximal and may have muscle hypertrophy. Peculiar intermittent pain syndrome in thigh, arms or back. Peculiar intermittent pain syndrome in thigh, arms or back. Phenotype otherwise is very similar to myotonic dystrophy. Phenotype otherwise is very similar to myotonic dystrophy.

25 Proximal Myotonic Myopathy Electrophysiology Effects of cooling, short and long exercise test not well documented. Effects of cooling, short and long exercise test not well documented.

26 Myotonia congenita Lack of weakness in most patients and absence of extramuscular abnormalities. Lack of weakness in most patients and absence of extramuscular abnormalities. AD (Thomsen’s disease): Julius Thomsen (1876) had the disease AD (Thomsen’s disease): Julius Thomsen (1876) had the disease AR(Becker’s disease): first described by Becker AR(Becker’s disease): first described by Becker Both arise from ClCN1 abnormality on Chr7q Both arise from ClCN1 abnormality on Chr7q Minor wasting and weakness in Becker and may also have transient periods of weakness. Minor wasting and weakness in Becker and may also have transient periods of weakness. Onset in infancy or early childhood. Onset in infancy or early childhood. Usually present with nonprogressive muscle stiffness. Usually present with nonprogressive muscle stiffness. Muscle hypertrophy is common (Herculean). Muscle hypertrophy is common (Herculean). Stiffness worsens after rest, cold and diminishes with exercise (warm up period). Stiffness worsens after rest, cold and diminishes with exercise (warm up period). Grip and percussion myotonia. Grip and percussion myotonia. CK slightly elevated in AD form, moderately elevated in AR form. CK slightly elevated in AD form, moderately elevated in AR form. Biopsy: may show lack of Type IIB fibres. Biopsy: may show lack of Type IIB fibres.

27 Myotonia congenita Young child with percussion myotonia of tongue.

28 Myotonia congenita Electrophysiology Widespread myotonic discharges, rare myopathic units in AR form. Widespread myotonic discharges, rare myopathic units in AR form. Muscle cooling in AD form may produce myotonic bursts of longer duration that maybe more easily elicited than at room temperature. Muscle cooling in AD form may produce myotonic bursts of longer duration that maybe more easily elicited than at room temperature. The short exercise test produces a CMAP immediately after exercise which recovers over 1-2 min with repeated CMAP recording every 10 seconds. The short exercise test produces a CMAP immediately after exercise which recovers over 1-2 min with repeated CMAP recording every 10 seconds. This is unlike paramyotonia congenita in which a decremental response recovers very slowly over many minutes. This is unlike paramyotonia congenita in which a decremental response recovers very slowly over many minutes. RNS causes decrement  15% (up to 50%) similar to MG RNS causes decrement  15% (up to 50%) similar to MG Repairs with brief exercise, but CMAP remains 10-15% lower Repairs with brief exercise, but CMAP remains 10-15% lower In ensuring 30 sec, decrement reappears. In ensuring 30 sec, decrement reappears. These responses to RNS and brief exercise characteristic of congenital myotonia. These responses to RNS and brief exercise characteristic of congenital myotonia. Rapid RNS (>10Hz) decrement >25% Rapid RNS (>10Hz) decrement >25%

29 Myotonia Congenita (Na channel) New syndrome that is K sensitive, SCN4A mutation on Chr17q(same abnormality as hyperkalemic periodic paralysis), see end of presentation for new syndromes. New syndrome that is K sensitive, SCN4A mutation on Chr17q(same abnormality as hyperkalemic periodic paralysis), see end of presentation for new syndromes.

30 Myotonia Fluctuans (K + Aggravated Myotonia) SCN4A mutation, AD SCN4A mutation, AD Symptoms occur after period of rest following exercise Symptoms occur after period of rest following exercise Stiffness often painful especially around chest. Stiffness often painful especially around chest. Marked variation in intensity of myotonia Marked variation in intensity of myotonia Myotonia aggravated by oral potassium or carbonic anhydrase inhibitors. Myotonia aggravated by oral potassium or carbonic anhydrase inhibitors.

31 Myotonia Permanens SCN4A mutation, AD SCN4A mutation, AD Similar to myotonia fluctuans except persistent rather than episodic Similar to myotonia fluctuans except persistent rather than episodic Symptoms occur after period of rest following exercise Symptoms occur after period of rest following exercise Stiffness often painful especially around chest. Stiffness often painful especially around chest. Marked variation in intensity of myotonia Marked variation in intensity of myotonia Myotonia aggravated by oral potassium or carbonic anhydrase inhibitors. Myotonia aggravated by oral potassium or carbonic anhydrase inhibitors.

32 Paramyotonia Congenita Eulenburg, Eulenburg, Stiffness usually affecting bulbofacial, neck & hand muscles. Stiffness usually affecting bulbofacial, neck & hand muscles. Stiffness is brought on by repeated contraction or exercise. Stiffness is brought on by repeated contraction or exercise. Stiffness is triggered by exposure to cold. Stiffness is triggered by exposure to cold. Infant noted to have prolonged eye closure after crying or face washed with cool water. Infant noted to have prolonged eye closure after crying or face washed with cool water.

33 Paramyotonia Congenita Electrophysiology Myotonia maybe more prominent in distal muscles. Myotonia maybe more prominent in distal muscles. Muscle cooling may have profound effect which is pathognomic: transient dense fibrillations appear with cooling which eventually disappear below 28°C; as further cooling occurs, all myotonic discharges completely disappear below 20°C giving way to paralysis of muscle. This may last up to an hour after muscle is warmed to room temperature. Muscle cooling may have profound effect which is pathognomic: transient dense fibrillations appear with cooling which eventually disappear below 28°C; as further cooling occurs, all myotonic discharges completely disappear below 20°C giving way to paralysis of muscle. This may last up to an hour after muscle is warmed to room temperature. Short exercise test may produce drop in CMAP which may show marked delay in recovery to baseline CMAP up to an hour (unlike myotonic dystrophy and Myotonia congenita); muscle cooling maybe necessary in some patients to bring out the decremental response. Short exercise test may produce drop in CMAP which may show marked delay in recovery to baseline CMAP up to an hour (unlike myotonic dystrophy and Myotonia congenita); muscle cooling maybe necessary in some patients to bring out the decremental response. RNS no decrement unless muscles cooled or after exercise. RNS no decrement unless muscles cooled or after exercise.

34 Hyperkalemic periodic paralysis Attacks of periodic weakness provoked by fasting, rest after exercise or cold. Attacks of periodic weakness provoked by fasting, rest after exercise or cold. Attacks are brief, lasting minutes to hours, and accompanied by hyporeflexia. Attacks are brief, lasting minutes to hours, and accompanied by hyporeflexia. K is usually elevated during attacks. K is usually elevated during attacks. Attack relieved by ingesting carbohydrates. Attack relieved by ingesting carbohydrates. Develop progressive weakness during adulthood. Develop progressive weakness during adulthood.

35 Hyperkalemic periodic paralysis Electrophysiology May not have myotonia between attacks. May not have myotonia between attacks. Rarely myopathic units. Rarely myopathic units. Myotonia seen early in the attack but disappear as weakness progresses. Myotonia seen early in the attack but disappear as weakness progresses. Muscle cooling ahs no effect. Muscle cooling ahs no effect. Short exercise test produces no decrement. Short exercise test produces no decrement. Long exercise test produces immediate increase in CMAP, especially if initial CMAP is low. Followed by progressive decline in CMAP by 50% over 20-40nminutes with most of decline in the first 20 minutes. Long exercise test produces immediate increase in CMAP, especially if initial CMAP is low. Followed by progressive decline in CMAP by 50% over 20-40nminutes with most of decline in the first 20 minutes. RNS causes no decrement unless after prolonged exercise. RNS causes no decrement unless after prolonged exercise.

36 Hypokalemic Periodic Paralysis Usually present in teenage yeas Usually present in teenage yeas Attacks can be prolonged, usually occurring on awakening and accompanied by hyporeflexia Attacks can be prolonged, usually occurring on awakening and accompanied by hyporeflexia K is low during attacks K is low during attacks Myotonia is never present. Myotonia is never present. Eventually, proximal myopathy. Eventually, proximal myopathy. Rarely associated mild sensory axonal polyneuropathy. Rarely associated mild sensory axonal polyneuropathy.

37 Hypokalemic Periodic Paralysis Electrophysiology Rarely associated mild sensory axonal polyneuropathy. Rarely associated mild sensory axonal polyneuropathy. Never myotonia Never myotonia Effects of cooling unknown. Effects of cooling unknown. Short exercise test causes no decrement. Short exercise test causes no decrement. Long exercise test produces immediate increase in CMAP, especially if initial CMAP is low. Followed by progressive decline in CMAP by 50% over 20-40nminutes with most of decline in the first 20 minutes. Long exercise test produces immediate increase in CMAP, especially if initial CMAP is low. Followed by progressive decline in CMAP by 50% over 20-40nminutes with most of decline in the first 20 minutes. RNS causes no decrement unless after prolonged exercise. RNS causes no decrement unless after prolonged exercise.

38 Other Muscle disorders associated with Myotonia Acid maltase deficiency Acid maltase deficiency inflammatory: polymyositis inflammatory: polymyositis congenital: myotubular myopathy congenital: myotubular myopathy drugs (clofibrate, statins, propranolol, fenoterol, terbutaline, colchicine, penicillamine, cyclopsorin) drugs (clofibrate, statins, propranolol, fenoterol, terbutaline, colchicine, penicillamine, cyclopsorin)

39 Exceptions to the Rule Channelopathies always thought of as disorders of fast inactivation, but newly discovered diseases due to slow inactivation. Hayward LJ, Sandoval GM, Cannon SC. Defective slow inactivation of sodium channels contributes to familial periodic paralysis Neurology, Apr 1999; 52: 1447.

40 Slow Inactivation of Na Channel (Heat Sensitive) Sodium currents by perforated patch clamp from wild-type (WT) and P1158S Na+ channels in transfected tsA201 cells at 22 and 32 °C. Test 10-millisecond pulses were given every 5 seconds to a potential between - 80 and 35 mV from the holding potential of -100 mV. WT Na+ currents at 22 °C (a) and 32 °C (b) are shown. P1158S Na+ currents showed a slower inactivation time course and slight late currents at both 22 °C (c) and 32 °C (c). I to V curves of Na+ current recorded by perforated patch clamp at 22 °C (e) and 32 °C (f) are also shown. Test 10-millisecond pulses were given every 5 seconds to a potential between -80 and 35 mV. Filled squares = WT, 22 °C; filled triangles = P1158S, 22 °C; open squares = WT, 32 °C; open triangles = P1158S, 32 °C.

41 Exceptions to the Rule Hypokalemic paralysis always thought of as Ca channel disease, new families discovered with mutation in SCN4A. Japanese family with AD heat induced myotonia and cold induced paralysis with hypokalemia. Bulman DE. Scoggan KA. van Oene MD. Nicolle MW. Hahn AF. Tollar LL. Ebers GC. A novel sodium channel mutation in a family with hypokalemic periodic paralysis. Neurology. 53(9):1932-6, 1999 Dec 10. Sugiura Y. Aoki T. Sugiyama Y. Hida C. Ogata M. Yamamoto T. Temperature- sensitive sodium channelopathy with heat-induced myotonia and cold- induced paralysis. Neurology. 54(11): , 2000 Jun 13

42 SCN4A Mutations Multiple Phenotypes KPP: Kalemic Periodic Paralysis PC: Paramyotonia Congenita PAM: Potassium Aggravated Myotonia

43 Exceptions to the Rule Multiorgan involvement : paramyotonia congenita with SCN4A mutation affecting cardiac repolarisation. Andersen-Tawil syndrome: mutation in K channel causes dysmorphic features, long QT, periodic paralysis. Exercise test is similar to periodic paralysis. New channel mutations. Pereon Y. Lande G. Demolombe S. Nguyen The Tich S. Sternberg D. Le Marec H. David A. Paramyotonia congenita with an SCN4A mutation affecting cardiac repolarization. Neurology. 60(2):340-2, 2003 Jan 28. M. R. Donaldson, J. L. Jensen, M. Tristani–Firouzi, R. Tawil, S. Bendahhou, W. A. Suarez, A. M. Cobo, J. J. Poza, E. Behr, J. Wagstaff, P. Szepetowski, S. Pereira, T. Mozaffar, D. M. Escolar, Y.- H. Fu, and L. J. Ptácek PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome Neurology : Katz JS. Wolfe GI. Iannaccone S. Bryan WW. Barohn RJ. The exercise test in Andersen syndrome. Archives of Neurology. 56(3):352-6, 1999 Mar S. Sampaolo, A. A. Puca, V. Nigro, V. Cappa, V. Sannino, G. Sanges, V. Bonavita, and G. Di Iorio Lack of sodium channel mutation in an Italian family with paramyotonia congenita Neurology : 1549

44 Andersen-Tawil Syndrome Syndactyly of the second and third toes on the left foot is evident, and toes on the right foot are dramatically shortened. The patient possesses a small, reduced chin and broad, flat nose— typical physical features associated with Andersen- Tawil syndrome. In the accompanying EKG, asterisks denote sinus beats, and overhead bar designates bidirectional ventricular tachycardia.

45 Exceptions to the Rule Compound heterozygotes confounding the diagnosis!!! S. Nagamitsu, T. Matsuura, M. Khajavi, R. Armstrong, C. Gooch, Y. Harati, and T. Ashizawa A "dystrophic" variant of autosomal recessive myotonia congenita caused by novel mutations in the CLCN1 gene Neurology :

46 The proband shows muscular hypertrophy of the quadriceps and hamstring and atrophy of the distal forearm and distal lower leg muscles. He has no "hatchet" facies or frontal baldness.


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