Correspondence

The EAST Syndrome and KCNJ10 Mutations

N Engl J Med 2009; 361:630-631August 6, 2009

Article

To the Editor:

Bockenhauer et al. (May 7 issue)1 report on a unique constellation of multiorgan signs and symptoms — epilepsy, ataxia, sensorineural deafness, and a renal salt-losing tubulopathy, which they term the EAST syndrome — associated with the homozygous missense mutations of the KCNJ10 gene encoding a potassium channel.

In the Discussion section, the authors propose that the seizures in the patients in their study were due to an extracellular accumulation of potassium in the absence of fully functional KCNJ10; this accumulation decreased the membrane potential and facilitated further excitations. This explanation is reasonable. However, another possibility — demyelinating disorders of the central nervous system — should not be ignored. KCNJ10 has been proved to be crucial for oligodendrocyte differentiation and in vivo myelination.2 Kcnj10 knockout mice have dysmyelination, extensive vacuolation, and apoptosis of glial cells, along with axon degeneration.2 The occurrence of epileptic seizures is a well-known clinical feature in the demyelination diseases of the central nervous system. Therefore, myelination disorders induced by mutant KCNJ10 probably account for the seizures in patients with the EAST syndrome as well.

Ming Shi, M.D., Ph.D.
Gang Zhao, M.D., Ph.D.
Xijng Hospital, Xi'an, China
zhaogang@fmmu.edu.cn

2 References

1. 1

   Bockenhauer D, Feather S, Stanescu HC, et al. Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med 2009;360:1960-1970
   Full Text | Web of Science | Medline

2. 2

   Neusch C, Rozengurt N, Jacobs RE, Lester HA, Kofuji P. Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination. J Neurosci 2001;21:5429-5438
   Web of Science | Medline

Author/Editor Response

Shi and Zhao emphasize the importance of KCNJ10 for brain function in the EAST syndrome. Clearly, there are differences between Kcnj10 in knockout mice and KCNJ10 in patients with the EAST syndrome; most obviously, in our study, mice died shortly after birth, whereas our patients lived. Similarly, the mice indeed showed extensive myelination defects, but routine brain magnetic resonance imaging in our patients was normal. This finding makes it difficult to ascribe seizures to demyelination. Whether this difference is due to differences between species or to the residual function of mutant KCNJ10 in preventing demyelination remains to be seen. Sequence variations in KCNJ10 have been shown to be associated with seizure susceptibility.1

Involvement of the central and peripheral nervous systems in the EAST syndrome appears to be complex. Studies of nerve-conduction velocity in our patients showed normal findings. Early and severe ataxia makes the assessment of mental involvement difficult. We did not observe obvious mental retardation in some of the patients. All neurologic findings, including hearing impairment, appeared to be nonprogressive. The identification of the EAST syndrome and careful clinical observations now allow us to study the role of KCNJ10 in brain and human physiology.2

Detlef Bockenhauer, M.D., Ph.D.
Great Ormond Street Hospital, London, United Kingdom

Horia C. Stanescu, M.D.
Robert Kleta, M.D., Ph.D.
University College London, London, United Kingdom
r.kleta@ucl.ac.uk

2 References

1. 1

   Buono RJ, Lohoff FW, Sander T, et al. Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility. Epilepsy Res 2004;58:175-183
   CrossRef | Web of Science | Medline

2. 2

   Bleich M. Membrane physiology -- bridging the gap between medical disciplines. N Engl J Med 2009;360:2012-2014
   Full Text | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Sascha Bandulik, Katharina Schmidt, Detlef Bockenhauer, Anselm A. Zdebik, Evelyn Humberg, Robert Kleta, Richard Warth, Markus Reichold. (2011) The salt-wasting phenotype of EAST syndrome, a disease with multifaceted symptoms linked to the KCNJ10 K+ channel. Pflügers Archiv - European Journal of Physiology 461:4, 423-435
   CrossRef