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Unusual white matter involvement in EAST syndrome associated with novel KCNJ10 mutations

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Abstract

Background

Epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) is a rare channelopathy due to KCNJ10 mutations. So far, only mild cerebellar hypoplasia and/or dentate nuclei abnormalities have been reported as major neuroimaging findings in these patients.

Methods

We analyzed the clinical and brain MRI features of two unrelated patients (aged 27 and 23 years) with EAST syndrome carrying novel homozygous frameshift mutations (p.Asn232Glnfs*14and p.Gly275Valfs*7) in KCNJ10, detected by whole exome sequencing.

Results

Brain MRI examinations at 8 years in Patient 1 and at 13 years in Patient 2 revealed a peculiar brain and spinal cord involvement characterized by restricted diffusion of globi pallidi, thalami, brainstem, dentate nuclei, and cervical spinal cord in keeping with intramyelinic edema. The follow-up studies, performed, respectively, after 19 and 10 years, showed mild cerebellar atrophy and slight progression of the brain and spinal cord T2 signal abnormalities with increase of the restricted diffusion in the affected regions.

Conclusion

The present cases harboring novel homozygous frameshift mutations in KCNJ10 expand the spectrum of brain abnormalities in EAST syndrome, including mild cerebellar atrophy and intramyelinic edema, resulting from abnormal function of the Kir4.1 inwardly rectifying potassium channel at the astrocyte endfeet, with disruption of water-ion homeostasis.

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References

  1. Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, Tobin J, Lieberer E, Sterner C, Landoure G, Arora R, Sirimanna T, Thompson D, Cross JH, van’t Hoff W, Al Masri O, Tullus K, Yeung S, Anikster Y, Klootwijk E, Hubank M, Dillon MJ, Heitzmann D, Arcos-Burgos M, Knepper MA, Dobbie A, Gahl WA, Warth R, Sheridan E, Kleta R (2009) Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med 360:1960–1970

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Scholl UI, Choi M, Liu T, Ramaekers VT, Hausler MG, Grimmer J, Tobe SW, Farhi A, Nelson-Williams C, Lifton RP (2009) Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proc Natl Acad Sci 106:5842–5847

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y (2010) Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev 90:291–366

    Article  PubMed  CAS  Google Scholar 

  4. Sicca F, Imbrici P, D’Adamo MC, Moro F, Bonatti F, Brovedani P, Grottesi A, Guerrini R, Masi G, Santorelli FM, Pessia M (2011) Autism with seizures and intellectual disability: possible causative role of gain-of-function of the inwardly-rectifying K + channel Kir4.1. Neurobiol Dis 43:239–247

    Article  PubMed  CAS  Google Scholar 

  5. Higashi K, Fujita A, Inanobe A, Tanemoto M, Doi K, Kubo T, Kurachi Y (2001) An inwardly rectifying K(+) channel, Kir4.1, expressed in astrocytes surrounds synapses and blood vessels in brain. Am J Physiol Cell Physiol 281:C922–C931

    Article  PubMed  CAS  Google Scholar 

  6. Sala-Rabanal M, Kucheryavykh LY, Skatchkov SN, Eaton MJ, Nichols CG (2010) Molecular mechanisms of EAST/SeSAME syndrome mutations in Kir4.1 (KCNJ10). J Biol Chem 285:36040–36048

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Tanemoto M, Abe T, Uchida S, Kawahara K (2014) Mislocalization of K + channels causes the renal salt wasting in EAST/SeSAME syndrome. FEBS Lett 588:899–905

    Article  PubMed  CAS  Google Scholar 

  8. Nwaobi SE, Cuddapah VA, Patterson KC, Randolph AC, Olsen ML (2016) The role of glial-specific Kir4.1 in normal and pathological states of the CNS. Acta Neuropathol 132:1–21

    Article  PubMed  CAS  Google Scholar 

  9. van der Knaap MS, Bugiani M (2017) Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol 134:351–382

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Bugiani M, van der Knaap MS (2017) Childhood white matter disorders: much more than just diseases of myelin. Acta Neuropathol 134:329–330

    Article  PubMed  Google Scholar 

  11. Neusch C, Rozengurt N, Jacobs RE, Lester HA, Kofuji P (2001) Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination. J Neurosci 21:5429–5438

    Article  PubMed  CAS  Google Scholar 

  12. Djukic B, Casper KB, Philpot BD, Chin L-S, McCarthy KD (2007) Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation. J Neurosci 27:11354–11365

    Article  PubMed  CAS  Google Scholar 

  13. Cross JH, Arora R, Heckemann RA, Gunny R, Chong K, Carr L, Baldeweg T, Differ A-M, Lench N, Varadkar S, Sirimanna T, Wassmer E, Hulton SA, Ognjanovic M, Ramesh V, Feather S, Kleta R, Hammers A, Bockenhauer D (2013) Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome. Dev Med Child Neurol 55:846–856

    Article  PubMed  PubMed Central  Google Scholar 

  14. Freudenthal B, Kulaveerasingam D, Lingappa L, Shah MA, Brueton L, Wassmer E, Ognjanovic M, Dorison N, Reichold M, Bockenhauer D, Kleta R, Zdebik AA (2011) KCNJ10 mutations disrupt function in patients with EAST syndrome. Nephron Physiol 119:p40–p48

    Article  PubMed  CAS  Google Scholar 

  15. Parrock S, Hussain S, Issler N, Differ A-M, Lench N, Guarino S, Oosterveld MJS, Keijzer-Veen M, Brilstra E, van Wieringen H, Konijnenberg AY, Amin-Rasip S, Dumitriu S, Klootwijk E, Knoers N, Bockenhauer D, Kleta R, Zdebik AA (2013) KCNJ10 mutations display differential sensitivity to heteromerisation with KCNJ16. Nephron Physiol 123:7–14

    Article  PubMed  Google Scholar 

  16. Abdelhadi O, Iancu D, Stanescu H, Kleta R, Bockenhauer D (2016) EAST syndrome: clinical, pathophysiological, and genetic aspects of mutations in KCNJ10. Rare Dis 4:e1195043

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Benfenati V, Ferroni S (2010) Water transport between CNS compartments: functional and molecular interactions between aquaporins and ion channels. Neuroscience 168:926–940

    Article  PubMed  CAS  Google Scholar 

  18. Rash JE (2010) Molecular disruptions of the panglial syncytium block potassium siphoning and axonal saltatory conduction: pertinence to neuromyelitis optica and other demyelinating diseases of the central nervous system. Neuroscience 168:982–1008

    Article  PubMed  CAS  Google Scholar 

  19. Dubey M, Bugiani M, Ridder MC, Postma NL, Brouwers E, Polder E, Jacobs JG, Baayen JC, Klooster J, Kamermans M, Aardse R, de Kock CPJ, Dekker MP, van Weering JRT, Heine VM, Abbink TEM, Scheper GC, Boor I, Lodder JC, Mansvelder HD, van der Knaap MS (2015) Mice with megalencephalic leukoencephalopathy with cysts: a developmental angle. Ann Neurol 77:114–131

    Article  PubMed  CAS  Google Scholar 

  20. Bugiani M, Dubey M, Breur M, Postma NL, Dekker MP, Ter Braak T, Boschert U, Abbink TEM, Mansvelder HD, Min R, van Weering JRT, van der Knaap MS (2017) Megalencephalic leukoencephalopathy with cysts: the Glialcam-null mouse model. Ann Clin Transl Neurol 4:450–465

    Article  PubMed  PubMed Central  Google Scholar 

  21. Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hubner CA, Jentsch TJ (2007) Leukoencephalopathy upon disruption of the chloride channel ClC-2. J Neurosci 27:6581–6589

    Article  PubMed  CAS  Google Scholar 

  22. van der Knaap MS, Boor I, Estévez R (2012) Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter oedema due to a defect in brain ion and water homoeostasis. Lancet Neurol 11:973–985

    Article  PubMed  Google Scholar 

  23. Depienne C, Bugiani M, Dupuits C, Galanaud D, Touitou V, Postma N, van Berkel C, Polder E, Tollard E, Darios F, Brice A, de Die-Smulders CE, Vles JS, Vanderver A, Uziel G, Yalcinkaya C, Frints SG, Kalscheuer VM, Klooster J, Kamermans M, Abbink TE, Wolf NI, Sedel F, van der Knaap MS (2013) Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurol 12:659–668

    Article  PubMed  CAS  Google Scholar 

  24. Menichella DM, Majdan M, Awatramani R, Goodenough DA, Sirkowski E, Scherer SS, Paul DL (2006) Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity. J Neurosci 26:10984–10991

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Patient samples were obtained from the “Cell Line and DNA Biobank from patients affected by Genetic Diseases” (Istituto Giannina Gaslini), member of Telethon Network of Genetic Biobanks (project no. GTB12001). This work was partially supported by unrestricted grants from “Cinque per mille e Ricerca Corrente, “Ministero della Salute” to MF and SL.

Author information

Author notes

  1. Mariasavina Severino and Susanna Lualdi contributed equally to this work.

Authors and Affiliations

  1. Neuroradiology Unit, Istituto Giannina Gaslini, Genoa, Italy

    Mariasavina Severino & Andrea Rossi

  2. UOSD, Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, Istituto Giannina Gaslini, Genoa, Italy

    Susanna Lualdi & Mirella Filocamo

  3. Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Istituto Giannina Gaslini, Via Gaslini 5, 16147, Genoa, Italy

    Chiara Fiorillo & Pasquale Striano

  4. Pediatric Clinic, Istituto Giannina Gaslini, Genoa, Italy

    Teresa De Toni

  5. Department of Neurosciences and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy

    Silvio Peluso & Giuseppe De Michele

  6. Center of Translational and Experimental Myology, Istituto Giannina Gaslini, Genoa, Italy

    Claudio Bruno

Authors
  1. Mariasavina Severino
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Contributions

MS: conception and design of the work, analysis and interpretation of brain MRI data. Drafting of manuscript, tables and figures. SL: acquisition, analysis and interpretation of mutation analysis data. Drafting of manuscript, tables and figures. CF: conception and design of the work. Collection and interpretation of patient 1 clinical data. Drafting the manuscript and revising critically for important intellectual content. PS: Collection and interpretation of patient 1 clinical data. Drafting the manuscript and revising critically for important intellectual content. TT: Collection and interpretation of patient clinical data. SP: Collection and interpretation of patient 2 clinical and neuroimaging data. GM: Drafting the manuscript and revising critically for important intellectual content. AR: acquisition of brain MRI data. Drafting the manuscript and revising critically. MF: acquisition of genetic results. Drafting the manuscript and revising critically for important intellectual content. CB: Drafting the manuscript and revising critically.

Corresponding author

Correspondence to Chiara Fiorillo.

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Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical statement

No ethic committee approval is required for this retrospective study report.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online Figure 1: Family pedigree of patients

415_2018_8826_MOESM2_ESM.tiff

Online Figure 2: Brain MRI and MR spectroscopy of Patient 1 at the age of 27 years (A-C) and of Patient 2 at the age of 23 years (D-F). Coronal (A, D) and sagittal (B, E) T2-weighted images reveal high signal in the upper cervical spinal cord (arrows). The brainstem is slightly smaller, and the corpus callosum is thin (thick arrows). Note reduction of the vermian volume (arrowheads). (C, E) Proton MR spectroscopy of the brainstem shows slightly reduced NAA in Patient 1 (empty arrow) and absence of lactate peaks in both patients

415_2018_8826_MOESM3_ESM.tiff

Online Figure 3: Brain MRI examinations performed at 8 years of age (A) and 28 years of age (B, C) in Patient 1. The first MRI reveals normal cerebellar volume (thick arrows, A), while the follow-up study demonstrates mild and slowly progressive cerebellar atrophy, more pronounced at the level of superior cerebellar hemispheres (thick arrows, B). Note the evolution of the T2-hyperintensity changes at the level of the globi pallidi (arrows) and thalami (arrowheads).

415_2018_8826_MOESM4_ESM.tiff

Online Figure 4: Brain MRI examinations performed at 13 years of age (A) and 23 years of age (B, C) in Patient 2. The first MRI reveals normal cerebellar volume (thick arrows, A), while the follow-up study demonstrates mild and slowly progressive cerebellar atrophy, more pronounced at the level of superior cerebellar hemispheres (thick arrows, B). Note the evolution of the T2-hyperintensity changes at the level of the midbrain (arrows) and globi pallidi (arrowheads).

Supplementary material 5 (DOCX 20 kb)

Supplementary material 6 (DOCX 130 kb)

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Severino, M., Lualdi, S., Fiorillo, C. et al. Unusual white matter involvement in EAST syndrome associated with novel KCNJ10 mutations. J Neurol 265, 1419–1425 (2018). https://doi.org/10.1007/s00415-018-8826-7

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  • DOI: https://doi.org/10.1007/s00415-018-8826-7

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