PMC4303471_01
Patient MRI, EEG and KCNT1 mutation information. (A-C) Initial studies demonstrated a severe delay in acquisition of normal myelination demonstrated on T2 weighted images (A, T2 axial image obtained at 3 years of age). However over time there was slow gradual progression of myelination (B, T2 axial image obtained at 7 years of age), demonstrated in the deep white matter (white arrows). Sagittal images (C, T1 weighted, 7 years of age) show microcephaly, and a shorted corpus callosum with a thin splenium. (D) EEG showing multifocal spike-wave discharges (bipolar longitudinal montage, epoch length 15 s, sensitivity 7 mcv/mm, tc 0.16 s, HFF 70 Hz). (E) A schematic of KCNT1 and the mutations recently described by Barcia et al. (purple text), Heron et al. (green text), McTague et al. (blue text) or in this study (black text and asterisk). Domain annotation is per Barcia et al. and Interpro. Note that nearly all amino acid changes are found in the cytoplasmic C-terminal protein domain.
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Indeed, the most recent MRI, performed at 7 years of age, has shown evidence of progression of myelination but at levels that are still severely reduced (Figure 1A-C), consistent with severely delayed myelination. Subsequent EEGs have continued to show an absence of normal background organization with multifocal epileptiform discharges during wakefulness and with activation in sleep, although without ictal events (Figure 1D). Using a custom-developed pipeline that integrates parental variant calls into the analysis of the affected child, a heterozygous de novo mutation in KCNT1 (MIM 608167; NM_020822.2) was identified in the proband (NM_020822: c.2794T>A, p.F932I; Figure 1E).