American Journal of Pathology & Research

Author(s): Adel Ekladious1,2*

1Faculty of health and medical sciences, University of Western Australia, 35 striling Highway, Perth WA 6009

2Royal Hobart Hospital, 8 Liverpool Street, Hobart, Tasmania 7000 Australia.

*Correspondence:

Adel Ekladious, Faculty of health and medical sciences, University of Western Australia, 35 striling Highway, Perth WA 6009; E-mail: egladiou@gmail.com.

Received: 07 Feb 2022; Accepted: 11 Mar 2022; Published: 15 Mar 2022

Citation: Adel Ekladious. Update on Muscle Channelopathy. American J Pathol Res. 2022; 1(1): 1-5

Case 1

23-year patient presented with difficulty of breathing after he finished a soccer match, in addition to back pain, he was transferred to the nearest hospital, and clinical examination was unremarkable. ECG was sinus rhythm, no ECG changes of ischemia or repolarization, chest X ray was normal, Oxygen saturation was 100% on room air, arterial blood gases was normal, the following blood tests were either normal or negative, Full Blood Count, Liver function tests, Kidney function, metabolic panel.

ESR, CRP, Iron study, B12, Folate, methylmalonic acid, haemocystein, exhaled nitric oxide, Lung function test including challenge with methacholine to exclude Bronchial Asthma and hypersensitive airways.

Patient was diagnosed as hyperventilation and discharged home, patient represented next day with difficulty to drink cold tea and chest tightness after 30 minutes training in the Gym.

Patient readmitted to the hospital for more investigation, basic investigation in addition to cardiac troponin, brain naturetic peptide (PNB), thyroid function tests, transthoracic echo, uncontracted CT head were done and all came normal, neurology senior registrar was consulted to see the patient, detailed neurological examination was unremarkable, examination of the fundus after pupillary dilation showed no abnormality, barium swallow ruled out any anatomical abnormality, patient was booked for esophageal motility study and arranged to be seen in outpatient clinic.

Two days later patient was admitted to the hospital with chest tightness, back pain, and unable to swallow cold orange juice, patient admitted to the hospital for further work up. Basic blood tests were repeated, Pan MRI was ordered, and esophageal motility study was done in his recent admission. All investigation came either negative or normal apart from CK, which was 1000 U/L (10- 80 u/l). Speech service was consulted to assess swallowing, which ruled out any esophageal or non-esophageal dysphagia, repeated CK came normal next day, the initial high CK was explained as a Lab error, patient was reassured and advised to be seen by a psychiatrist for functional disorder.

Psychatric assessment did not support the diagnosis of functional disorder and advised that patient discharged from his clinic and should be seen by a multidisciplinary team should he developed any further symptoms. Patient readmitted to the hospital one week later as he could not catch his breath and not able to move his left side of his jaw, urgent MRI stroke protocol was done and did not reveal any restricted diffusion.

MRI with Gadolinium did not show any enhancement, CK came 900u/l (10-80). A medical student was asked to take a detailed history from the patient as well as a detailed neurological and systemic examination. Patient gave a history that his brother had similar symptoms before affecting mainly his legs. Medical student found patient after exercise developed difficulty to relax his face, and repeated CK is 1110U/I.

Patient was taken to the electrophysiology lab where nerve conduction study was normal, but EMG diagnosed electrical myotonia of the jaw and thoracic muscles, patient started on oral Acetazolamide And counselled for genetic testing which came positive for SCN4A confirming the diagnosis of Paramyotonia Congentia.

Case 2

22-year-old patient presented with palpitation and shortness of breath, seen in ED where cardiac examination showed bradycardia of 50/min with no drop in blood pressure, JVP was not elevated.

Rest of cardiac examination was normal, ECG did not show any ischemic changes, prolonged Holter monitor for 4 days did not show any arrythmias, cardiac enzymes and BNP were normal, thyroid function test, electrolytes, iron study, B12, folate were normal, chest X ray and transthoracic echo cardiogram did not show any abnormalities, patient reassured and sent home. Two weeks later patient was readmitted with palpitation and weakness of both legs. Examination revealed weakness in both hip flexors 3/5 with normal sensation, diminished knee reflexes and dawngoing planters, ECG showed polymorphic ventricular extrasystole and marginally prolonged Q-T Of 480ms (360-460ms), the following blood test were normal or negative, FBC, LFT, U, E, Metabolic panel, Thyroid function test, cardiac troponin, BNP, Vasculitis panel, autoimmune panel, septic screen. Acetylcholine receptor antibodies, Anti MUSK antibody, MRI for whole spine was normal, CSF was non-reactive, transthoracic Echocardiogram was normal, next day patient improved spontaneously. Patient was sent home and outpatient appointment was arranged for exercise test.

During exercise test patient had to stop in stage 1 (Bruce protocol) because of weakness in both legs and ventricular tachycardia, exercise was stopped, patient given 2 mg IV metoprolol and admitted to ICU for observation. Patient was Asymptomatic in ICU, after 24 hours observation, patient moved to medical ward for more work up, detailed examination showed patient had dysmorphic features, which encompass short stature, low set ears, microgantheia, short palpebral fissures, and short nose with fullness along the nasel bridge. Broad forehead, high arched palate. Bulbous tip of the nose, cleft palate, triangular face, syndactyly of the 2nd and 3rd toes. Digit clinodactyly, cognitive assessment showed deficits in executive functions and abstract reasoning, patient deemed unable to make decisions, family was invited for a meeting to discuss future management, it was decided that patient would benefit from implantable cardiac defibrillator, and genetic testing to exclude Andersen – Tawil Syndrome. Genetic sequencing confirmed positivity for KCNJ2, also patient started on acetazolamide. Other members of the family offered genetic testing but declined.

Discussion

Skeletal muscle Channelopathy are a family of rare genetic neuromuscular disorders causing impaired muscular contraction, relaxation or both caused by dysfunction of sarco-lemmal ion channels that is essential for muscular membrane excitability caused by a mutation in Voltage – gated sodium, Potassium, Chloride and calcium channels. The diagnosis is often delayed as symptoms are episodic and usually difficult to be described by patients, although symptoms are benign but it can cause disability, embarrassment of the patients, social isolation and rarely can cause death if it affected the larynx causing laryngospasm and cyanosis and loss of consciousness and commonly interpreted as a seizure [1,2]. Membrane depolarization hyperexcitability can cause myotonia and hypo excitability cause weakness and paralysis, channelopathy encompassed periodic paralysis and non-dystrophic myotonia [3]. Periodic paralysis encompasses hypokalemic periodic paralysis, hyperkalemic periodic paralysis and Andersen – Tawil Syndrome. Non-dystrophic Myotonia could be Myotonia Congenita or paramyotonia congenita.

Periodic Paralysis

Periodic hypokalemic, hyperkalemic and Andresen – Tawil syndrome (ATS) are all autosomal dominant disorders, Hyperkalemic periodic paralysis is caused by mutation in the Sodium channel gene SCN4A. Hypokalemic periodic paralysis is caused by mutation in Calcium Channel gene CACNA1S on chromosome IQ31. Andresen -Tawil Syndrome is caused by mutation in the potassium channel Gene KCNJ2 on chromosome 17Q23. Severity of weakness can vary from mild to severe weakness, jerks are diminished. Sensation will be intact, skeletal muscles are only affected, straited muscles (Bowel and bladder) are not affected, over time patient will develop irreversible proximal myopathy, patient also can suffer from fatigue and myalgia. Hypokalemia can induce ECG changes in the form of depressed ST Segment and U wave, which are indication of intravenous potassium 40 ml KCL in 1 liter saline with rate of 10ml/hour, examination between attack’s is usually normal.

Patient with hyperkalemia might develop myotonia, weakness might last minutes to hours, triggered by high potassium food and cold drinks. Patient might be able to walk on even ground but can’t climb stairs, sometime weakness might be task specific like writing with one arm or kicking the ball with one leg, also weakness is specific to rest after exercise. Potassium sparing diuretics can trigger weakness.

Hypokalemic periodic Paralysis is the most common skeletal channelopathy, although respiratory and cardiac muscles are not affected, life threatening arrythmia and respiratory failure had been reported.

Mutant channels induce an inward cation leakage current which decreased the threshold of muscle fibers to aberrant depolarization in response to increase intracellular potassium and decrease extracellular potassium, that is why this patient should be monitored after normalization of the serum potassium to make sure that they did not develop rebound hyperkalemia due to movement of intracellular potassium to the extracellular compartment. Patient with periodic hypokalemia should have a work up to exclude renal tubular acidosis, Gitelman syndrome, hyperaldosteronism, Cushing syndrome, potassium losing diuretics, thiazide and frusemide intake, vasoactive intestinal peptide VIPoma, diarrhea and vomiting, salt losing Nephropathy, Fanconi syndrome.

Thyrotoxicosis occurs in 85 % of patients with hypokalemia and is will be autosomal dominant with CACNA1 mutant, the rest is autosomal recessive with SCN4A mutation. Korean J Pediatr had recently identified altered subcellular distribution of a calcium – activated potassium channel in skeletal muscle cells of patients with hypokalemic periodic paralysis.

Andresen -Tawil Syndrome

Is a multisystem disorder characterized by dysmorphic features. Cardiac arrythmia due to conduction defects, prolonged Q-T, episodic paralysis in the first or second decade of life. Commonly associated with hypokalemia and uncommonly hyperkalemia, precipitating factors are similar to hypo and hyperkalemia. Fixed proximal myopathy usually occurs, myotonia usually does not occur, sudden cardiac death had been reported. Most patients will need antiarrhythmic medications, up to 15% of patients will need implantable cardiac defibribrillator, expert opinions recommend patient should have annular review by an expert electrophysiology cardiologist and prolonged Holter monitor, long corrected Q-T interval is the most common abnormalities, U wave amplitude is the most sensitive ECG.

ECG can differentiate between conduction blocks in Andresen- Tawil Syndrome and polymorphic tachycardia in myotonia muscle biopsy frequently shows tubular aggregates and nonspecific myopathic changes [4,5].

Non-Dystrophic myotonia

Majority of patients with non-dystrophic myotonia have primary or secondary loss of membrane chloride conductance due to reduction in the resting membrane potential. Non-dystrophic myotonia are now known to be caused by dysfunction of skeletal muscle ion channels. Which include myotonia congenita, paramyotonia congenitia and sodium channel myotonia. Common symptoms are delayed relaxation of muscles following muscles contraction, or exercise, EMG showed repetitive muscles fiber after discharge.

Myotonia Congenita is caused by a mutation in the skeletal muscle Chloride channel gene either autosomal dominant or recessive, (CLCN-1). Legs usually affected more than face and arm and this explained the frequent falls in Myotonia Congenita (MC). Symptoms triggered by prolonged rest after exercise, and change in temperature, warm environment can alleviate myotonia, warm up phenomena is characteristic of myotonia (exercise after developing myotonia will abort it), weakness is usually brief and disappear with exercise, patient usually develop hypertrophy of calf muscles [6,7].

Paramyotonia Congenita

It is characterized by marked sensitivity to cold, face and hands are affected more than legs, warm environment relieved myotonia, patients would not helped by exercise (negative warm up phenomena) [8]. In fact, patients with paramyotonia will get worse with exercise and develop paradoxical myotonia. Which is characteristic for paramyotonia, patients usually develop a prolonged time of weakness. Not uncommonly misdiagnosed as hyperkalemic periodic paralysis, muscle hypertrophy can be generalized, usually it is autosomal dominant and SCN4A mutated [9,10].

Malignant hyperthermia

Malignant hyperthermia is a serious channelopathy where the mutation RYR1 causes hypersensitive channels which causes efflux of calcium from sarcoplasmic stores to myoplasm causing muscle rigidity and hyperthermia in response to volatile anesthetics and depolarizing muscle relaxants, this causes depletion of ATP and upregulates glycogenolysis causing metabolic acidosis. Increased oxygen consumption and carbon dioxide production leading to sever hypoxia, hypercapnia and rhabdomylosis, hyperkalemia and multiorgan failure [10,11].

Diagnosis and differential diagnosis

Diagnosis depends mainly on history and normal examination in between attacks and confirmation with genetic study, because the disease is very rare and patient find difficulty to describe the symptoms. Usually the diagnosis is delayed, clinicians should concentrate on the history rather than on the examination, family history is extremely important as most of the channelopathy are autosomal dominant apart from Myotonia congenita which could be autosomal dominant or recessive, EMG plays important role in confirming electrical myotonia [12,13].

Important clue in the history are, when was the first-time patient had the symptoms, which part of the body affected first, legs or limb and face, what triggered the symptoms, is it at rest after exercise, or associated with lower body temperature, medication whether potassium sparing or potassium depleting diuretics. How long for was the weakness, did exercise help the weakness or made it worse (Warm up phenomena or paradoxical myotonia in paramyotonia congenita), did patient have pain and fatigue [14]. Were the bladder or bowel involved (usually not as they are not skeletal muscles), did patient lose alertness or consciousness (usually no otherwise seizure will be the differential diagnosis specially if all attacks are stereotyped), if patient can walk on flat even ground but can’t not climb stairs, does patient have proximal myopathy from long standing recurring attacks, ictal potassium and CK is important clue to the diagnosis, patient with myotonia congenita can be diagnosed from the waiting room as they when arise after seated position, they have difficulty because of myotonia and stiffness and once they reach the examination room, they become normal, examination might show myotonic eye lid or hand grip [15]. Patient with paramyotenia congentia will develop paradoxical myotonia after exercise, Patients with Andersen-Tawil syndrome will have dysmorphic features and usually they have cardiac symptoms from conduction blocks, occasionally they have myotonia, but classic symptoms are hypokalemic periodic paralysis.

Differential diagnosis including but not limited to pomp’s disease which is a glycogen storage disease characterised by muscle weakness, organomegaly in adult form of the disease, patient will have hyperkaliemia. Episodic ataxia are a group of genetic disease chacterised by paroxysmal truncal ataxia and incoordination which usually last from minutes to hours, most have an autosomal dominant pattern, diagnosis can be confirmed by genetic study for KCNA1 and CACNA1A mutation [16-20].

Treatment

Skeletal muscle channelopathy are incurable but symptoms can be ameliorated by removing triggering factors like exercise or rest after exercise which trigger myotonia, it is important to find a balance of exercise, which could not provoke symptoms. Patient with paramyotonia congentia may require rest period after balanced exercise, patients with myotonia should avoid sudden movement and instead increase severity of exercise very gradually, and patients should avoid cold weather by appropriate clothing.

Medications, which help symptoms, are mainly Sodium channel blockers, mainly Mexiletine that is first line for non-dystrophic myotonia, Lamotrigine that is anticonvulsant, voltage gated sodium channel blocker whose mode of action is slow binding to the fast-inactivated voltage gated sodium channel, and shifting of the voltage gated dependance of inactivation to more negative potentials [21-27].

Carbamazepine

A well stablished anticonvulsant for decades and showing promising effects on many studies.

Flecainide

Class 1c antiarrhythmic, contraindicated in patients who had structural heart disease.

Ranolazine

Mode of action enhances slow inactivation of voltage gated sodium channels and blocks persistent Voltage dependent sodium inward current.

Acetazolamide

It is a carbonic anhydrase inhibitor and can prevent periodic paralysis; it is useful for patients with periodic paralysis and myotonia in the same time like hyperkalemic periodic paralysis. Side effect included renal calculi and renal tubular acidosis.

Summary and Conclusion

Patients with skeletal muscle channelopathy will have common symptoms of rare diseases. Diagnosis is mainly on the history including detailed family history and not on the examination.

All common investigation for skeletal muscle channelopathy is negative or normal. Hypokalemia with normal acid balance is a clue that patient might have genetic hypokalemic periodic paralysis.

Secondary causes for hypo or hyperkalemia should be ruled out including and not limiting to potassium losing diuretics, primary hyperaldosteronism, paraneoplastic Cushing syndrome, distal renal tubular acidosis, Fanconi syndrome, use of laxative, salt losing nephropathy, use of corticosteroids, syndrome of inappropriate ADH, Gittelman syndrome, potassium rich food, potassium sparing diretics, adrenal insufficiency.

Episodic movement disorder can be confused with skeletal muscle channelopathy, Patients with skeletal muscle channelopathy could be manifested by intermittent fatigue syndrome. Dysmorphic features should not be ignored, as it is one of the manifestations of Andersen-Tawil Syndrome, although routine blood tests are normal in skeletal muscle channelopathy, genetic testing is fundamental to diagnose and confirm the disease [28-30].

1. Hanna EmaMG. Skeletal Muscle Channelopathy. Oxford textbook of neuromuscular disorders. 2014.
2. Matthews E, Silwal A, Sud R. Skeletal muscle channelopathy: rare disorders with common pediatric symptoms. J peditar. 2017; 188: 181-856.
3. Andresen ED, Krasilinikoff PA, Overvad H. Intermittent muscular weakness and multiple developmental anomalies. A new sundrome?. Acta peditar scand. 1971; 60: 559-564.
4. Mazzanti A, Trancuccio A. Risk smartification in in Andersen–tawil Syndrome type 1. Am Coll cardiol 2020; 75: 1772-1784.
5. Marrow Jm, Matthews E, Raja rayan DL, et al. muscle MRI reveals distincit abonrmalties in genetically proven non- Dystrophic myotonia. Neuromuscular discord. 2013; 23: 637- 646.
6. Russel SH, Hirsch NP. Anaethesia and myotonia. Br J Anaesth. 1994; 72.
7. Farbu E, Softeland E, Bindoff LA. Anaesthetic complications associated with myotonia congenita: Case study and comprasion with other myotonic disorders. Acta Anesthesia Scand. 2003; 47: 630-634.
8. Trivedi JR, Bundy B, Statland J, et al. Non-dystrophic myotonia: prospective study of objective and patient reported outcomes, brain. 2013; 136: 2189-2200.
9. Milone M, Mc Evoy KM, Sorenson Ej, et al. Myotonia associated with Caveolin-3 mutation. Muscle nerve. 2012; 45: 897-900.
10. Holm-Yildiz S, Witting N, Dahlqvist J, et al. permanent muscle weakness in hypokalemic periodic paralysis. Neurology. 2020; 95: 342-352.
11. Mattewa E, Fiaho D, Tan SV, et al. The non–dystrophic myotonias: Molecular Pathogenesis, Diagnosis and Treatment. Brain. 2010; 133: 9-22.
12. Mc Clatchy AL, Van den Bergh, Pericak- vance MA, et al. Temerature- sensitive mutations in the 111-1V cytoplasmic. Loop region of the skeletal muscule sodium channel gene in paramyotonia congentia. Cell. 1992; 68: 769-774.
13. Jurkat-Rott K, Lehmann-Horn F, Elbaz A, et al. A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol genet. 1994; 3: 1415-1419.
14. Fontaine B, Khurana TS, Hoffman EP, et al. Hyperkalemic periodic paralysis and the adult muscule sodium channel alpha- subunit gene. Science. 1990; 250: 1000-1002.
15. Trip J, Drost G, Ginjaar HB, et al. Redefining the clinical phenotypes of non-dystrophic myotonic syndromes. J Neurol Neurosurg Psychiatry. 2009; 80: 647-652.
16. Miller TM, Dias Da Silva MR, Miller HA, et al. Correlating Phenotype and genotype in periodic paralysis. Neurology. 2004; 63: 1647-1655.
17. Charles G, Zheng C, Lehmann-Horn F, et al. Characterization of hyperkalemic perdoic paralysis: a survey of genetically diagnosed Individuals. J neurol. 2013; 260: 2606-2613.
18. Yoon G, Oberoi S, Tristani-Firouzi M, et al. Andresen-Tawil Syndrome: prospective Cohort analysis and expansion of the phenotype. Am J Med Genet A. 2006; 140: 312-321.
19. Cheng CJ, Lin SH, Lo YF, et al. Identification and Functional Characterization of kir2.6 Mutation Associated with non- familial hypokalemic periodic paralysis. Journal of Biological Chemistry. 2011; 286: 27425-27435.
20. Ahmed A, Simmons Z. Isaacs syndrome: a review. Muscle Nerve. 2015; 52: 5-12.
21. Loruss S, Kline D, Bartlett A, et al. Open–label trial of ranolazine for the treatment of paramyotonia congenita. Muscle Nerve. 2019; 59: 240-243.
22. Kwiecinski H, Ryniewicz b, Ostrzycki A. treatment of mytonia with antiarrhythmic drugs. Acta Neurol Scand. 1992; 86: 371-375.
23. Sheela SR. Myotonia congentia: response to carbamazepine. Indian Pediatr. 2000; 37: 1122-1125.
24. De Bellis M, Camerino DC, Desaphy JF. Toward precision medicine in myotonic syndromes. Oncotarget. 2017; 8: 14270-14280.
25. Vicart S, Franques J, Bouchour F, et al. Efficacy and safety of Mexiletine in non-dystrophic Myotonia: a randomized, double–blind, placebo–controlled, cross–over study. Neuromuscul Disord. 2021.
26. Lo Monaco M, D Amico A, Luigetti M, et al. Effect of Mexiletine on transitory depression motor action potential in recessive myotonia congita. Clin Neurophysiol. 2015; 126: 399-403.
27. Lehmann-Horn F, Jurkat- Rott K, Rudel R. Diagnostics and Therpay of Muscule Channelopathy- Guidelines of the ULM Muscule Centre. Acta Myol. 2008; 27: 89-113.
28. Miller TM. Differential diagnosis of myotonic disorders.Muscule Nerve. 2008; 37: 293-299.
29. Statland JM, Bundy BN, Wang Y, et al. Mexiletine for symptoms and signs in non-dystrophic myotonia: a randomised contolled trial. JAMA. 2021; 308: 1357-1365.
30. Arnold WD, Kline D, Sanderson A, et al. open -label trial of ranolazine for the treatment of myotonia congentia. Neurology. 2017; 89: 710-713.