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Table of Contents
Year : 2019  |  Volume : 7  |  Issue : 3  |  Page : 60-61

A sneak peek into channelopathies

Department of General Medicine (Geriatric Wing), JSS Medical College, Mysore, Karnataka, India

Date of Web Publication15-Jul-2019

Correspondence Address:
Dr. Pratibha Pereira
JSS Medical College, Mysore, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AJIM.AJIM_15_19

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How to cite this article:
Pereira P. A sneak peek into channelopathies. APIK J Int Med 2019;7:60-1

How to cite this URL:
Pereira P. A sneak peek into channelopathies. APIK J Int Med [serial online] 2019 [cited 2020 Jul 16];7:60-1. Available from: http://www.ajim.in/text.asp?2019/7/3/60/262741

Channelopathies are a group of familial diseases associated featuring myotonia and/or hypotonic paralysis, caused by defective ion channels. Hypotonic variants are associated with hyperkalemia, hypokalemia, or normokalemia. Basically, there are transmembrane glycoprotein pores which work on cell excitability and electrical signaling working on two types of gated channels: voltage gated and ligand gated. They can be phenotype heterogeneity or genetic heterogeneity.[1]

These disorders are caused by mutation in genes encoding the ion channels.

Mutation of ion channel can cause alteration in the activation, ion selectivity, and inactivation of the channel. This can result in abnormal gain of function or loss of function.

Hyperkalemic periodic paralysis involves mutations in the SCN4A sodium channel protein that regulates sodium entry during muscle contraction.

Hypokalemic periodic paralysis (hypoPP) involves the gene encoding L-type calcium channel and also SCN4A sodium channel. There is impaired EC coupling.

Malignant hyperpyrexia presents in a dramatic hypermetabolic state (tachycardia, tachypnea, muscle spasm, and hyperpyrexia) triggered by anesthesia. Although it can occur in number of settings (e.g., congenital myopathies and metabolic myopathies), it is associated with mutations of genes encoding L-type voltage-dependent calcium channel (notably the ryanodine receptor) exposure to anesthetic agent where mutant receptor allows uncontrolled sarcoplasmic calcium efflux.

Mutations in the ion channels typically autosomal dominant disorder involving ion channel protein (NA, K or Ca) transport or accessory molecules that conduct the electrical current that controls myocardial contraction.

Whereas the specific clinical manifestation of channelopathies is quite variable, one common feature is that manifestations tend to be intermittent or paroxysmal, occurs in epilepsy and migraine.

Typically, neurologic channelopathies are inherited in an autosomal dominant fashion and cause paroxysmal disturbance of neurological function, although the impairment of function can become fixed with time. The ion channel mutation-related diseases have increased our understanding of pathomechanisms that are relevant to common neurological diseases such as migraine and epilepsy.

Channelopathies of the nervous system are epilepsy, focal epilepsy syndromes, cerebellar ataxia, and episodic ataxia.

Inherited channelopathies of peripheral nerves are pain syndromes such as paroxysmal extreme pain disorder, skeletal muscle channelopathies, sodium channel mutations (Paramyotonia congenita (PMC) and Sodium channel myotonias (SCMS)), and periodic paralysis.[2]

The case series presented here are a group of inherited periodic paralysis. They comprise three conditions such as hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and Andersen–Tawil syndrome.

Hypokalemic periodic paralysis is the most common form of periodic paralysis and is characterized by episodes of flaccid muscle weakness that occurs in association with low serum potassium level. The overwhelming majority of mutations in hypoPP, whether in calcium or in sodium channel, occur in the voltage-sensing region of the channel. The mutations open an abnormal cation leak pathway through the voltage sensor itself, separate from the main pore of the channel – the gating pore current. The association with hyperkalemia probably reflects in part a positive feedback loop, whereby depolarization leads to potassium efflux which results in a further depolarization.

  Thyrotoxic Periodic Paralysis Top

Thyrotoxic periodic paralysis (TPP) is a rare condition causing attacks indistinguishable from hypoPP but in the presence of thyrotoxicosis.

Thyroid hormone-mediated sensitization of adrenergic receptors leads to stimulation of the Na+/K+ ATPase channels in the skeletal muscles with a resultant influx of potassium into the cells. Thyroid hormone also regulates expression of the gene encoding Kir 2.6, the inwardly rectifying potassium channel which plays a part in the maintenance of resting membrane potential.[3] A mutation in this gene alters muscle membrane excitability, decreasing the ability of muscles to respond to stimulation, and has been found in over a third of the patients with TPP.

The authors have presented a series of cases of periodic paralysis.

Periodic paralyses belong to a group of muscle diseases called channelopathies, which present with painless objective generalized muscle weakness without exertion.[4] TPP is caused by an intracellular shift of potassium precipitated by increased levels of thyroid hormones. It is characterized by episodes of weakness and paralysis. TPP has been predominantly reported in young male patients of Asian descent.[5] It is extremely rare in other ethnicities.[1] A large carbohydrate meal, stress, strenuous exercise, alcohol, acute upper respiratory infection, a high-salt diet, menstruation, and cold temperatures have been reported to precipitate these attacks.[6]

Here, they have reported a series of cases of nine male patients who had presented with acute flaccid paralysis in the setting of hypokalemia. Subsequently, the patients were found to have secondary hypokalemic periodic paralysis – five diagnosed with dengue infection and four had thyrotoxicosis.

Five of these patients had dengue positive. The authors have brought out a very interesting diagnosis of hypokalemic periodic paralysis in particular secondary hypokalemic periodic paralysis as a differential in the setting of acute, painless, flaccid motor paralysis, especially in young patients with no significant family history or risk factors for stroke or Guillain–Barré syndrome.[7] This is important as recognizing it early and treating it can prevent further episodes.[8]

The authors have also have shown the association of thyrotoxicosis and hypokalemic periodic paralysis. Thyrotoxic hypokalemic periodic paralysis is characterized by acute attacks, weakness, hypokalemia, and thyrotoxicosis of various etiologies. TPP belongs to a group of muscle diseases called channelopathies, which present with painless generalized muscle weakness without exertion. TPP can be precipitated by a large carbohydrate meal, stress, strenuous exercise, alcohol, a high-salt diet, menstruation, and cold temperatures. Rarely, steroids such as dexamethasone can also precipitate a TPP attack.[9]

Mutations in potassium channel Kir 2, 6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. These transient attacks resemble those of patients with familial hypokalemic periodic paralysis (hypoKPP) and resolve with treatment of the underlying hyperthyroidism. Due to the phenotype similarity of these conditions, it is hypothesized that TPP might also be a channelopathy. A new gene has been identified an inwardly rectifying potassium (KIR) channel, Kir2 6. Thus, the channel is nearly identical to Kir 2.2. This is expressed in skeletal muscles and transcriptionally regulated by thyroid hormone.

They have recommended routine estimation of thyroid levels to be done as the initial line of investigation even if features of thyrotoxicosis are absent.[10] In the presence of acute febrile illness, ordering serology for dengue, after ruling out thyrotoxicosis, is the preferred approach in India.

  References Top

Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL. Harrison's manual of medicine.  Back to cited text no. 1
Ryan DP, da Silva MR, Soong TW, Fontaine B, Donaldson MR, Kung AW, et al. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell 2010;140:88-98.  Back to cited text no. 2
Graves TD, Hanna MG. Neurological channelopathies. Postgrad Med J 2005;81:20-32.   Back to cited text no. 3
Spillane J, Kullmann DM, Hanna MG. Genetic neurological channelopathies: Molecular genetics and clinical phenotypes. J Neurol Neurosurg Psychiatry 2016;87:37-48.   Back to cited text no. 4
Felix R. Channelopathies: Ion channel defects linked to heritable clinical disorders. J Med Genet 2000;37:729-40.   Back to cited text no. 5
Ryan DP, Ptácek LJ. Episodic neurological channelopathies. Neuron 2010;68:282-92.   Back to cited text no. 6
Kullmann DM, Waxman SG. Neurological channelopathies: New insights into disease mechanisms and ion channel function. J Physiol 2010;588:1823-7.   Back to cited text no. 7
Matthews E, Labrum R, Sweeney MG, Sud R, Haworth A, Chinnery PF, et al. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 2009;72:1544-7.   Back to cited text no. 8
Ahamed R, McCalley S, SuleAA. Steroids and thyrotoxicosis precipitate periodic paralysis. Cureus 2018;10:e2106.   Back to cited text no. 9
Wu F, Mi W, Cannon SC. Bumetanide prevents transient decreases in muscle force in murine hypokalemic periodic paralysis. Neurology 2013;80:1110-6.  Back to cited text no. 10


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