Unusual white matter involvement in EAST syndrome associated with novel KCNJ10 mutations
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.
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.
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.
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.
KeywordsKir4.1 KCNJ10 EAST syndrome SeSAME syndrome Brain MRI Diffusion-weighted imaging Intramyelinic edema Astrocytopathy Channelopathy Whole exome sequencing Frameshift variants
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.
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.
Compliance with ethical standards
Conflicts of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
No ethic committee approval is required for this retrospective study report.
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