New Territory Opened by Periodic Paralysis Associated with Mitochondrial DNA Mutation

EDITORIAL New territory opened by periodic paralysis associated with mitochondrial DNA mutation

Robert L. Ruff, MD, PhD Science is an exploration of knowledge. Early world indirectly altered. In the previously discussed disor- Stephen Cannon, MD, maps did not recognize large land masses until some- ders of skeletal membrane excitability, including PhD one first observed them. The report by Auré et al.1 periodic paralysis, the pathophysiology could be describes new territory in the field of periodic paral- explained by direct alterations of the operations of ysis and other disorders of skeletal muscle membrane mutated ion channels. Episodes of periodic paralysis Correspondence to excitability. The muscle membrane has to balance on resulted from membrane depolarization that was a Dr. Ruff: [email protected] a knife edge between excessive excitability manifest by direct consequence of altered channel function. Auré conditions such as myotonia, and inexcitability, as et al.1 did not find any of the previously recognized – Neurology® 2013;81:1806–1807 occurs intermittently in periodic paralysis.2 4 Under- channelopathy mutations associated with periodic standing disorders of altered muscle membrane excit- paralysis. Instead, they found consistent mutations of ability is important because the knowledge gained mitochondrial DNA. They identified the MT-ATP6 leads to increased understanding of how excitable m.9185T.C p.Leu220Pro mutation that was previ- membranes function and may suggest ways of treat- ously associated with Leigh syndrome. In addition, ing membrane disorders that can involve many tis- they also discovered the MT-TL1 m.3271T.Cmuta- sues, including brain, peripheral nerve, and skeletal tion that caused MELAS (mitochondrial encephalop- and cardiac muscle. athy with lactic acidosis and stroke-like episodes) Pathophysiologic investigations have focused on syndrome in the one subject who had MELAS. They the roles of specific ion channels in maintaining nor- studied the effect of these mitochondrial DNA muta- mal skeletal muscle membrane excitability. Chloride tions in cultured fibroblasts and observed defects of channels enhance membrane stability, and the first complexes V and I as well as oxidative stress. The pre- identified channelopathies producing myotonia were cise pathophysiologic connection between the altered loss-of-function chloride channel mutations.2–4 intracellular metabolism and periodic paralysis pheno- Gain-of-function sodium channel mutations disturb- type is not clear; in patient-derived fibroblasts, how- ing the normal balance of channel opening (activa- ever, the mitochondrial mutations resulted in altered tion), closing, and inactivation can also produce potassium ion permeability associated with plasma myotonia.2–4 Paralytic episodes in periodic paralysis membrane depolarization. are associated with membrane depolarization that The possibility of indirect effects on channel func- inactivates sodium channels leading to membrane tion was suggested by prior studies of hypokalemic peri- inexcitability.2–4 The channels associated with periodic paralysis. Type 1 hypokalemic periodic paralysis, odic paralysis include CACNA1S (calcium), SCN4A which is associated with mutations involving CAC- (sodium), and KCNJ2 (inward rectifier potassium NA1S, and a related disorder, thyrotoxic periodic paral- channel).2,3 That similar phenotypes can result from ysis, are associated with reduction in the outward mutations of genes encoding different ion channels current component of a specific potassium channel emphasizes the important interplay among ion chan- and reduced voltage-gated sodium channel current.6 Re- nels involved with membrane excitability. Mutations ductions in these currents may be epiphenomena, of sodium and calcium channels associated with although an expected consequence of reduced voltage- hypokalemic periodic paralysis share a common gated sodium current, reduced membrane excitability,4 mechanistic pathway because the mutations permit is observed in type 1 hypokalemic periodic paralysis.7 an alternative current pathway through the mutant A causative role for these anomalous currents in channels that can depolarize the membrane.5 the susceptibility to periodic paralysis is supported The new pathophysiologic territory defined by by the observation of analogous functional changes Auré et al.1 was that membrane excitability could be in conventional channelopathies of skeletal muscle.

See page 1810 From the Louis Stokes Cleveland Department of Veterans Affairs Medical Center (R.L.R.), Departments of Neurology and Neurosciences, Case Western Reserve University, Cleveland, OH; and Department of Neurology & Neurotherapeutics (S.C.), University of Texas Southwestern Medical Center, Dallas, TX. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial.

1806 © 2013 American Academy of Neurology ª"NFSJDBO"DBEFNZPG/FVSPMPHZ6OBVUIPSJ[FESFQSPEVDUJPOPGUIJTBSUJDMFJTQSPIJCJUFE In type 2 hypokalemic periodic paralysis, the sodium DISCLOSURE channel mutations increase resting-state inactivation, The authors report no disclosures relevant to the manuscript. Go to which would be expected to reduce the baseline so- Neurology.org for full disclosures. 2–4 dium channel current. There is also evidence that REFERENCES reduced inward rectifier potassium current contrib- 1. Auré K, Dubourg O, Jardel C, et al. Episodic weakness utes to the hypokalemic periodic paralysis phenotype. due to mitochondrial DNA MT-ATP6/8 mutations. Neu- Inward rectifier potassium channel mutations occur rology 2013;81:1810–1818. in both thyrotoxic periodic paralysis8 and Andersen- 2. Cannon SC. Pathomechanisms in channelopathies of skeletal – Tawil syndrome,9 which includes a periodic paralysis muscle and brain. Annu Rev Neurosci 2006;29:387 415. 3. Lehmann-Horn F, Rüdel R, Jurkat-Rott K. Nondytrophic phenotype. In an animal model of hypokalemic myotonias and periodic paralysis. In: Engel AG, Franzini- periodic paralysis, partial block of inward rectifier Armstrong C, editors. Myology, 3rd ed. New York: potassium channels leads to hypokalemia-induced McGraw-Hill; 2004:1257–1300. depolarization.10 Altered action of insulin on the 4. Shapiro BE, Ruff RL. Disorders of skeletal muscle mem- inward rectifier potassium channel contributes to brane excitability: myotonia congenita, paramyotonia con- insulin-induced paralysis in type 1 hypokalemic genita, periodic paralysis and related syndromes. In: Katirji B, Kaminski HJ, Preston D, Ruff RL, Shapiro BE, periodic paralysis.11 Additionally, increasing inward rec- editors. Neuromuscular Disorders in Clinical Practice. Bos- tifier potassium channel current may be the mechanism ton: Butterworth-Heinemann; 2002:987–1021. of action of acetazolamide-induced improvement of 5. Wu F, Mi W, Hernández-Ochoa EO, et al. A calcium chan- symptoms in hypokalemic periodic paralysis.12 All of nel knock-in mutant (CaV1.1-R528H) mouse model of hypo- these changes would be exacerbated by the inward cur- kalemic periodic paralysis. J Clin Invest 2012;122:4580–4591. rent conducted by an alternative pathway in both type 6. Puwanant A, Ruff RL. INa and IKir are reduced in type 1 (calcium) and type 2 (sodium) hypokalemic periodic 1 hypokalemic and thyrotoxic periodic paralysis. Muscle Nerve 2010;42:315–327. 5 paralysis. 7. Links TP, van der Hoeven JH. Muscle fiber conduction In contrast to the possibility that altered func- velocity in arg1239his mutation in hypokalemic periodic tion of inward rectifier potassium channels and paralysis. Muscle Nerve 2000;23:296. reduced voltage-gated sodium channel current con- 8. Ryan DP, Dias da Silva MR, Soong TW, et al. Mutations in tribute to the membrane depolarization in type potassium channel Kir2.6 cause susceptibility to thyrotoxic – 1 hypokalemic periodic paralysis, the work of Auré hypokalemic periodic paralysis. Cell 2010;140:88 98. 9. Bendahhou S, Fournier E, Sternberg D, et al. In vivo and et al.1 leaves little doubt that altered mitochondrial in vitro functional characterization of Andersen’s syn- function contributed to the periodic paralysis phe- drome mutations. J Physiol 2005;565:231–241. notype in their subjects. The challenge for future 10. Struyk AF, Cannon SC. Paradoxical depolarization of explorers is to determine how oxidative stress alters Ba21-treated muscle exposed to low extracellular K1: in- membrane function. sights into resting potential abnormalities in hypokalemic paralysis. Muscle Nerve 2008;37:326–337. AUTHOR CONTRIBUTIONS 11. Ruff RL. Insulin acts in hypokalemic periodic paralysis by 1 Robert L. Ruff: drafting/revising the manuscript, study concept or design, reducing inward rectifier K current. Neurology 1999;53: analysis or interpretation of data, acquisition of data, study supervision. 1556–1563. Stephen Cannon: drafting/revising the manuscript. 12. Tricarico D, Mele A, Camerino DC. Carbonic anhydrase inhibitors ameliorate the symptoms of hypokalaemic periodic STUDY FUNDING paralysisinratsbyopeningthemuscularCa21-activated-K1 No targeted funding reported. channels. Neuromuscul Disord 2006;16:39–45.

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