Identification of a novel de novo p.Phe932Ile KCNT1 mutation in a patient with leukoencephalopathy and severe epilepsy

Abstract

Background: More than half of patients with genetic leukoencephalopathies remain without a specific diagnosis; this is particularly true in individuals with a likely primary neuronal etiology, such as those in which abnormal white matter occurs in combination with severe epilepsy.

Patient: A child with a severe early infantile epileptic encephalopathy and abnormal myelination underwent whole exome sequencing.

Results: Whole exome sequencing identified a heterozygous de novo mutation in KCNT1, a sodium-gated potassium channel gene.

Conclusions: Severely delayed myelination was anecdotally reported in previous patients with KCNT1 mutations. This case reinforces that KCNT1 sequencing should be included in an investigation of patients with severely delayed myelination and epilepsy.

Keywords: KCNT1; delayed myelination; leukoencephalopathy; myoclonic.

Figure 1

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.