Multiple Sclerosis and Related Disorders (2014) 3, 141–142
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
COMMENTARY
Chloride channel loss of function linked with white matter disease Russell C. Dalen Neuroimmunology group, Institute for Neuroscience and Muscle Research, the Children's Hospital at Westmead, University of Sydney, Australia In a recent report in the Lancet Neurology, a rare genetic leukoencephalopathy associated with the chloride channel mutations has provided improved understanding into the role of ion and water homeostasis in white matter function (Depienne et al., 2013). This study provides further rationale for the use of therapies that target ion channels in neuroprotection for multiple sclerosis. The starting point for the study by Depienne et al. (2013) was seven patients with a leukoencephalopathy with a highly specific MRI pattern. The patients had a leukoencephloaphy with specific involvement of the middle cerebellar peduncles, midbrain cerebral peduncles, and the posterior limbs of the internal capsule. The patients all had characteristic diffusion weighted imaging and decreased apparent diffusion coefficient (ADC) values in the posterior limbs of the internal capsule showing restricted diffusion, suggesting myelin vacuolation which represents a radiological ‘flag’ of this diagnostic entity (Depienne et al., 2013). Six of the seven patients investigated with this radiological phenotype had homozygous or compound heterozygous mutations in the chloride channel, CLCN2. The six individuals with CLCN2 mutations had cerebellar ataxia as a common feature, plus a variety of associated features including spasticity, visual loss and cognitive problems. The authors provided evidence that CLCN2 mutations result in loss of function of the chloride channel ClC-2 (Depienne et al., 2013). CLCN2 is expressed in all glia, and is enriched in astrocytic endfeet (Depienne et al., 2013). Mutant mice without functional ClC-2 have a leukoencephalopathy and intramyelinic oedema (Blanz et al., 2007).
n
Tel.: +61298450000. E-mail address: [email protected]
2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.09.006
This human genetic chloride channelopathy described by Depienne et al. provides insight into the role of ion channels and water homeostasis, which was eloquently demonstrated using functional models and radiological correlates. Astrocytes are central to the process of maintaining brain ion and water homeostasis, which is essential to action potential generation and therefore impulse conduction (Skaper, 2011). There are now emerging human and animal models directly linking ion homeostasis (in this case chloride and secondary potassium siphoning) and intramyelinic oedema (Depienne et al., 2013; Skaper, 2011). This genetic disease provides ongoing support for the use of therapies that target ion channels as potential neuroprotective strategies in white matter disorders such as multiple sclerosis (Skaper, 2011; Waxman, 2008). Although there has been much progress in understanding the inflammatory mechanisms of MS and interventions to target inflammation, other strategies have focussed on microglia ion channels that represent specific targets of drugs for neuroprotection (Skaper, 2011). Excessive accumulation of ions such as Na + , K + , Ca2 + and Cl has been linked to neurodegeneration in multiple sclerosis (Friese et al., 2007). Amiloride, a blocker of proton-gated acid-sensing ion channels (ASICs) was an effective neuroprotective agent in the animal model experimental allergic encephalomyelitis (Friese et al., 2007). Arun et al. (2013) have recently translated this finding to humans and shown increased ASIC expression in axons of chronic inactive lesions from patients with progressive MS post mortem. Amiloride was used in 14 patients with primary progressive MS and imaging comparisons were made pretreatment and on treatment. On amiloride, there was a significant reduction in normalized annual whole brain volume loss and less diffusion tensor imaging abnormalities,
142 supporting a rationale for randomised controlled trials using amiloride in neuroprotection (Arun et al., 2013). Sodium channel blockade has also been proposed as a therapeutic target for MS neuroprotection (Waxman, 2008), and other microglia ion channels including chloride channels have been proposed as targets to reduce neurodegeneration in MS (Skaper, 2011), although it is noted some of these agents have additional anti-inflammatory effects, therefore the potential beneficial effects may be multi-factorial (Virgili et al., 2011). However, a recent double blind study using lamotrigine in secondary progressive MS patients noted a significant reduction in brain volume in patients treated with lamotrigine that reversed on stopping treatment, demonstrating the complex relationship between ion channels, water and brain volume that will be essential to consider in the design of future studies investigating MS neuroprotection (Kapoor et al., 2010). Of course, 4-aminopyridine, a voltage-gated potassium channel blocker, has been used to relieve neurological symptoms in chronic neurological diseases such as MS (Sedehizadeh et al., 2012), and may also improve visual function in demyelinating optic neuropathy (Horton et al., 2013). The novel but rare genetic chloride channelopathy described by Depienne et al. provides further insight into the role of microglia ion channels in maintaining water homeostasis, and furthers the rationale for neuroprotective strategies that target ion channels.
Conflict of interest statement There is no conflict of interest.
References Arun T, Tomassini V, Sbardella E, de Ruiter MB, Matthews L, Leite MI, et al. Targeting ASIC1 in primary progressive multiple
R.C. Dale sclerosis: evidence of neuroprotection with amiloride. Brain 2013;136(Pt 1):106–15. Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hubner CA, et al. Leukoencephalopathy upon disruption of the chloride channel ClC-2. Journal of Neuroscience 2007;27(24):6581–9. Depienne C, Bugiani M, Dupuits C, Galanaud D, Touitou V, Postma N, et al. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurology 2013;12(7):659–68. Friese MA, Craner MJ, Etzensperger R, Vergo S, Wemmie JA, Welsh MJ, et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nature Medicine 2007;13(12):1483–9. Horton L, Conger A, Conger D, Remington G, Frohman T, Frohman E, et al. Effect of 4-aminopyridine on vision in multiple sclerosis patients with optic neuropathy. Neurology 2013;80(20):1862–6. Kapoor R, Furby J, Hayton T, Smith KJ, Altmann DR, Brenner R, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurology 2010;9(7):681–8. Sedehizadeh S, Keogh M, Maddison P. The use of aminopyridines in neurological disorders. Clinical Neuropharmacology 2012;35 (4):191–200. Skaper SD. Ion channels on microglia: therapeutic targets for neuroprotection. CNS & Neurological Disorders – Drug Targets 2011;10(1):44–56. Virgili N, Espinosa-Parrilla JF, Mancera P, Pasten-Zamorano A, Gimeno-Bayon J, Rodriguez MJ, et al. Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis. Journal of Neuroinflammation 2011;8:149. Waxman SG. Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis-current status. Nature Clinical Practice Neurology 2008;4(3):159–69.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
COMMENTARY
Chloride channel loss of function linked with white matter disease Russell C. Dalen Neuroimmunology group, Institute for Neuroscience and Muscle Research, the Children's Hospital at Westmead, University of Sydney, Australia In a recent report in the Lancet Neurology, a rare genetic leukoencephalopathy associated with the chloride channel mutations has provided improved understanding into the role of ion and water homeostasis in white matter function (Depienne et al., 2013). This study provides further rationale for the use of therapies that target ion channels in neuroprotection for multiple sclerosis. The starting point for the study by Depienne et al. (2013) was seven patients with a leukoencephalopathy with a highly specific MRI pattern. The patients had a leukoencephloaphy with specific involvement of the middle cerebellar peduncles, midbrain cerebral peduncles, and the posterior limbs of the internal capsule. The patients all had characteristic diffusion weighted imaging and decreased apparent diffusion coefficient (ADC) values in the posterior limbs of the internal capsule showing restricted diffusion, suggesting myelin vacuolation which represents a radiological ‘flag’ of this diagnostic entity (Depienne et al., 2013). Six of the seven patients investigated with this radiological phenotype had homozygous or compound heterozygous mutations in the chloride channel, CLCN2. The six individuals with CLCN2 mutations had cerebellar ataxia as a common feature, plus a variety of associated features including spasticity, visual loss and cognitive problems. The authors provided evidence that CLCN2 mutations result in loss of function of the chloride channel ClC-2 (Depienne et al., 2013). CLCN2 is expressed in all glia, and is enriched in astrocytic endfeet (Depienne et al., 2013). Mutant mice without functional ClC-2 have a leukoencephalopathy and intramyelinic oedema (Blanz et al., 2007).
n
Tel.: +61298450000. E-mail address: [email protected]
2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.09.006
This human genetic chloride channelopathy described by Depienne et al. provides insight into the role of ion channels and water homeostasis, which was eloquently demonstrated using functional models and radiological correlates. Astrocytes are central to the process of maintaining brain ion and water homeostasis, which is essential to action potential generation and therefore impulse conduction (Skaper, 2011). There are now emerging human and animal models directly linking ion homeostasis (in this case chloride and secondary potassium siphoning) and intramyelinic oedema (Depienne et al., 2013; Skaper, 2011). This genetic disease provides ongoing support for the use of therapies that target ion channels as potential neuroprotective strategies in white matter disorders such as multiple sclerosis (Skaper, 2011; Waxman, 2008). Although there has been much progress in understanding the inflammatory mechanisms of MS and interventions to target inflammation, other strategies have focussed on microglia ion channels that represent specific targets of drugs for neuroprotection (Skaper, 2011). Excessive accumulation of ions such as Na + , K + , Ca2 + and Cl has been linked to neurodegeneration in multiple sclerosis (Friese et al., 2007). Amiloride, a blocker of proton-gated acid-sensing ion channels (ASICs) was an effective neuroprotective agent in the animal model experimental allergic encephalomyelitis (Friese et al., 2007). Arun et al. (2013) have recently translated this finding to humans and shown increased ASIC expression in axons of chronic inactive lesions from patients with progressive MS post mortem. Amiloride was used in 14 patients with primary progressive MS and imaging comparisons were made pretreatment and on treatment. On amiloride, there was a significant reduction in normalized annual whole brain volume loss and less diffusion tensor imaging abnormalities,
142 supporting a rationale for randomised controlled trials using amiloride in neuroprotection (Arun et al., 2013). Sodium channel blockade has also been proposed as a therapeutic target for MS neuroprotection (Waxman, 2008), and other microglia ion channels including chloride channels have been proposed as targets to reduce neurodegeneration in MS (Skaper, 2011), although it is noted some of these agents have additional anti-inflammatory effects, therefore the potential beneficial effects may be multi-factorial (Virgili et al., 2011). However, a recent double blind study using lamotrigine in secondary progressive MS patients noted a significant reduction in brain volume in patients treated with lamotrigine that reversed on stopping treatment, demonstrating the complex relationship between ion channels, water and brain volume that will be essential to consider in the design of future studies investigating MS neuroprotection (Kapoor et al., 2010). Of course, 4-aminopyridine, a voltage-gated potassium channel blocker, has been used to relieve neurological symptoms in chronic neurological diseases such as MS (Sedehizadeh et al., 2012), and may also improve visual function in demyelinating optic neuropathy (Horton et al., 2013). The novel but rare genetic chloride channelopathy described by Depienne et al. provides further insight into the role of microglia ion channels in maintaining water homeostasis, and furthers the rationale for neuroprotective strategies that target ion channels.
Conflict of interest statement There is no conflict of interest.
References Arun T, Tomassini V, Sbardella E, de Ruiter MB, Matthews L, Leite MI, et al. Targeting ASIC1 in primary progressive multiple
R.C. Dale sclerosis: evidence of neuroprotection with amiloride. Brain 2013;136(Pt 1):106–15. Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hubner CA, et al. Leukoencephalopathy upon disruption of the chloride channel ClC-2. Journal of Neuroscience 2007;27(24):6581–9. Depienne C, Bugiani M, Dupuits C, Galanaud D, Touitou V, Postma N, et al. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurology 2013;12(7):659–68. Friese MA, Craner MJ, Etzensperger R, Vergo S, Wemmie JA, Welsh MJ, et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nature Medicine 2007;13(12):1483–9. Horton L, Conger A, Conger D, Remington G, Frohman T, Frohman E, et al. Effect of 4-aminopyridine on vision in multiple sclerosis patients with optic neuropathy. Neurology 2013;80(20):1862–6. Kapoor R, Furby J, Hayton T, Smith KJ, Altmann DR, Brenner R, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurology 2010;9(7):681–8. Sedehizadeh S, Keogh M, Maddison P. The use of aminopyridines in neurological disorders. Clinical Neuropharmacology 2012;35 (4):191–200. Skaper SD. Ion channels on microglia: therapeutic targets for neuroprotection. CNS & Neurological Disorders – Drug Targets 2011;10(1):44–56. Virgili N, Espinosa-Parrilla JF, Mancera P, Pasten-Zamorano A, Gimeno-Bayon J, Rodriguez MJ, et al. Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis. Journal of Neuroinflammation 2011;8:149. Waxman SG. Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis-current status. Nature Clinical Practice Neurology 2008;4(3):159–69.
