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Abstract
Epilepsy, Ataxia, Sensorineural deafness and Tubulopathy (EAST syndrome), also known as Seizures, Sensorineural deafness, Ataxia, Mental retardation, and Electrolyte imbalance (SeSAME syndrome) is a rare autosomal recessive syndrome due to homozygous missense mutations of the KCNJ10 gene.
We report two siblings from India, both presented with early-onset epilepsy, developmental delay, hearing impairment, ataxia, and electrolyte imbalances suggestive of tubulopathy - Gitelman syndrome.
First born boy, presented at age 9 years, with onset of epilepsy at 12 months of age. The younger sibling, a girl, presented at 2½ years, with infrequent febrile and afebrile generalized seizures. Both demonstrated delayed milestones and had mild sensorineural hearing loss.
They had multiple brain magnetic resonance imaging studies with relatively similar distribution of abnormalities involving the dentate nuclei, brainstem, thalami, basal ganglia, and cerebral white matter, with mild progression of the neuroimaging findings over time. Epilepsy was refractory in both of them at last follow up.
The constellation of multi-organ involvement was characteristic of EAST syndrome, and mutation analysis of the KCNJ10 gene confirmed the diagnosis. Neuroimaging showed characteristic features that supported the diagnoses.
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Copyright (c) 2023 Lokesh Lingappa, Nihaal Reddy, Dandu Ravi Varma, Bindu Madhavi Paruchuri, Ramesh Konanki, Robert Kleta, Bockenhauer D
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References
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1. Reichold M, Zdebik AA, Lieberer E, Rapedius M, Schmidt K, Bandulik S, Sterner C, Tegtmeier I, Penton D, Baukrowitz T et al. KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proc Natl Acad Sci U S A. 2010;107:14490–5. doi: 10.1073/pnas.1003072107. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922599/
2. Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, Tobin J, Lieberer E, Sterner C, Landoure G, et al..et al. Epilepsy, Ataxia, Sensorineural Deafness, Tubulopathy, and KCNJ10 Mutations. N Engl J Med 2009;360:1960–70. doi: 10.1056/NEJMoa0810276. Available from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398803/
3. Moritani T, Smoker WR, Sato Y, Numaguchi Y, Westesson PL. Diffusion-weighted imaging of acute excitotoxic brain injury. AJNR Am J Neuroradiol 2005;26:216-28. Available from http://www.ajnr.org/content/26/2/216.long
4. Freudenthal B, Kulaveerasingam D, Lingappa L, Shah MA, Brueton L, Wassmer E, et al. KCNJ10 Mutations Disrupt Function in Patients with EAST Syndrome. Nephron Physiol 2011;119:40–8. doi: 10.1159/000330250.Available from https://pubmed.ncbi.nlm.nih.gov/21849804/
5. Scholl UI, Choi M, Liu T. Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proceedings of the. 2009. Available: https://www.pnas.org/content/106/14/5842.short accessed 9 May 2020
6. Celmina M, Micule I, Inashkina I, Audere M, Kuske S, Pereca J, Stavusis J, Pelnena D, Strautmanis J. EAST/SeSAME syndrome: Review of the literature and introduction of four new Latvian patients. Clin Genet 2019;95:63–78. Available from https://pubmed.ncbi.nlm.nih.gov/29722015/
7. Scholl UI, Dave HB, Lu M, Farhi A, Nelson-Williams C, Listman JA,Lifton RP. SeSAME/EAST syndrome—phenotypic variability and delayed activity of the distal convoluted tubule. Pediatr Nephrol 2012;27:2081–90. doi: 10.1007/s00467-012-2219-4. Available from https://pubmed.ncbi.nlm.nih.gov/22907601/
8. Stivaros S. How the imaging investigation of EAST syndrome points towards the future of radiological multi-parametric phenotyping of a genetic disease. Developmental Medicine & Child Neurology 2013;55:783–4. doi: 10.1111/dmcn.12189. Available from https://pubmed.ncbi.nlm.nih.gov/23924081/
9. Benatar M. Neurological potassium channelopathies. QJM 2000;93:787-97. doi: 10.1093/qjmed/93.12.787. Available from Available from https://pubmed.ncbi.nlm.nih.gov/11110585/
10. Severino M, Lualdi S, Fiorillo C, Striano P, De Toni T, Peluso S, De Michele G, Rossi A, Filocamo M, Bruno C. Unusual white matter involvement in EAST syndrome associated with novel KCNJ10 mutations. J Neurol 2018;265:1419–25. doi: 10.1007/s00415-018-8826-7. Available from https://pubmed.ncbi.nlm.nih.gov/29666984/
11. Nadella RK, Chellappa A, Subramaniam AG, More RP, Shetty S, Prakash S, Ratna N, Vandana VP, Purushottam M, Saini J, et al. Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance. Hum Genomics 2019;13:53. doi: 10.1186/s40246-019-0236-0. Available from https://pubmed.ncbi.nlm.nih.gov/31640787/
12. Morin M, Forst AL, Pérez-Torre P, Jiménez-Escrig A, Barca-Tierno V, García-Galloway E, Warth R, Moreno JLL, Moreno-Pelayo MA.et al. Novel mutations in the KCNJ10 gene associated to a distinctive ataxia, sensorineural hearing loss and spasticity clinical phenotype. Neurogenetics 2020;21:135–43. doi: 10.1007/s10048-020-00605-6. Available from https://pubmed.ncbi.nlm.nih.gov/32062759/
13. Zhang H, Zhu L, Wang F, Wang R, Hong Y, Chen Y, Zhu B, Gao Y, Luo H, Zhang X, et al. Novel KCNJ10 Compound Heterozygous Mutations Causing EAST/SeSAME-Like Syndrome Compromise Potassium Channel Function. Front Genet 2019;10:912. doi: 10.3389/fgene.2019.00912. Available from
https://pubmed.ncbi.nlm.nih.gov/31781151/
References
2. Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, Tobin J, Lieberer E, Sterner C, Landoure G, et al..et al. Epilepsy, Ataxia, Sensorineural Deafness, Tubulopathy, and KCNJ10 Mutations. N Engl J Med 2009;360:1960–70. doi: 10.1056/NEJMoa0810276. Available from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398803/
3. Moritani T, Smoker WR, Sato Y, Numaguchi Y, Westesson PL. Diffusion-weighted imaging of acute excitotoxic brain injury. AJNR Am J Neuroradiol 2005;26:216-28. Available from http://www.ajnr.org/content/26/2/216.long
4. Freudenthal B, Kulaveerasingam D, Lingappa L, Shah MA, Brueton L, Wassmer E, et al. KCNJ10 Mutations Disrupt Function in Patients with EAST Syndrome. Nephron Physiol 2011;119:40–8. doi: 10.1159/000330250.Available from https://pubmed.ncbi.nlm.nih.gov/21849804/
5. Scholl UI, Choi M, Liu T. Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proceedings of the. 2009. Available: https://www.pnas.org/content/106/14/5842.short accessed 9 May 2020
6. Celmina M, Micule I, Inashkina I, Audere M, Kuske S, Pereca J, Stavusis J, Pelnena D, Strautmanis J. EAST/SeSAME syndrome: Review of the literature and introduction of four new Latvian patients. Clin Genet 2019;95:63–78. Available from https://pubmed.ncbi.nlm.nih.gov/29722015/
7. Scholl UI, Dave HB, Lu M, Farhi A, Nelson-Williams C, Listman JA,Lifton RP. SeSAME/EAST syndrome—phenotypic variability and delayed activity of the distal convoluted tubule. Pediatr Nephrol 2012;27:2081–90. doi: 10.1007/s00467-012-2219-4. Available from https://pubmed.ncbi.nlm.nih.gov/22907601/
8. Stivaros S. How the imaging investigation of EAST syndrome points towards the future of radiological multi-parametric phenotyping of a genetic disease. Developmental Medicine & Child Neurology 2013;55:783–4. doi: 10.1111/dmcn.12189. Available from https://pubmed.ncbi.nlm.nih.gov/23924081/
9. Benatar M. Neurological potassium channelopathies. QJM 2000;93:787-97. doi: 10.1093/qjmed/93.12.787. Available from Available from https://pubmed.ncbi.nlm.nih.gov/11110585/
10. Severino M, Lualdi S, Fiorillo C, Striano P, De Toni T, Peluso S, De Michele G, Rossi A, Filocamo M, Bruno C. Unusual white matter involvement in EAST syndrome associated with novel KCNJ10 mutations. J Neurol 2018;265:1419–25. doi: 10.1007/s00415-018-8826-7. Available from https://pubmed.ncbi.nlm.nih.gov/29666984/
11. Nadella RK, Chellappa A, Subramaniam AG, More RP, Shetty S, Prakash S, Ratna N, Vandana VP, Purushottam M, Saini J, et al. Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance. Hum Genomics 2019;13:53. doi: 10.1186/s40246-019-0236-0. Available from https://pubmed.ncbi.nlm.nih.gov/31640787/
12. Morin M, Forst AL, Pérez-Torre P, Jiménez-Escrig A, Barca-Tierno V, García-Galloway E, Warth R, Moreno JLL, Moreno-Pelayo MA.et al. Novel mutations in the KCNJ10 gene associated to a distinctive ataxia, sensorineural hearing loss and spasticity clinical phenotype. Neurogenetics 2020;21:135–43. doi: 10.1007/s10048-020-00605-6. Available from https://pubmed.ncbi.nlm.nih.gov/32062759/
13. Zhang H, Zhu L, Wang F, Wang R, Hong Y, Chen Y, Zhu B, Gao Y, Luo H, Zhang X, et al. Novel KCNJ10 Compound Heterozygous Mutations Causing EAST/SeSAME-Like Syndrome Compromise Potassium Channel Function. Front Genet 2019;10:912. doi: 10.3389/fgene.2019.00912. Available from
https://pubmed.ncbi.nlm.nih.gov/31781151/