Severe Neonatal Epileptic Encephalopathy and KCNQ2 Mutation: Neuropathological Substrate?

Abstract

Background: Neonatal convulsions are clinical manifestations in a heterogeneous group of disorders with different etiology and outcome. They are attributed to several genetic causes.

Methods: We describe a patient with intractable neonatal seizures who died from respiratory compromise during a status epilepticus.

Results: This case report provides electroencephalogram (EEG), MRI, genetic analysis, and neuropathological data. Genetic analysis revealed a de novo heterozygous missense mutation in the KCNQ2 gene, which encodes a subunit of a voltage-gated potassium channel. KCNQ2 gene mutation is associated with intractable neonatal seizures. EEG, MRI, data as well as mutation analysis have been described in other KCNQ2 cases. Post-mortem neuropathological investigation revealed mild malformation of cortical development with increased heterotopic neurons in the deep white matter compared to an age-matched control subject. The new finding of this study is the combination of a KCNQ2 mutation and the cortical abnormalities.

Conclusion: KCNQ2 mutations should be considered in neonates with refractory epilepsy of unknown cause. The mild cortical malformation is an important new finding, though it remains unknown whether these cortical abnormalities are due to the KCNQ2 mutation or are secondary to the refractory seizures.

Keywords: KCNQ2 mutation; MRI; cortical dysplasia; ion channel gene defect; neonatal; neonatal seizures.

Figure 1

Electroencephalogram recording on day 25. The EEG shows a non-synchronized pattern with suppressions, multifocal sharp waves, and a focal epileptic seizure in the left hemisphere.

Figure 2

MRI findings on day 7. (A) T1-weighted MRI (inversion recovery) shows discrete swelling of the basal nuclei and thalamus. (B) T2-weighted MRI shows a decreased signal in basal nuclei and thalamus.

Figure 3

Histopathology of the frontal cortex shows mild malformation of cortical development. (A) H&E staining at low magnification shows a normal six-layered architecture of the cortex. (B) At high magnification of the cortex and cortical boundary, heterotopic neurons displaced to the white matter make it difficult to distinguish between the gray and white matter border (H&E). (C) In the frontal cortex of a control subject, the gray–white matter junction appears sharply demarcated (H&E). (D) Abnormal clusters of SMI31-immunoreactive neurons (arrow) are visible in the deep cortical layers. (E,F) The deep white matter (>500 mm from the cortical border) shows increased cellularity by heterotopic neurons [(E), stain against the microtubule associated protein 2 (MAP2); (F) stain against extranuclear RNA identifying neurons]. (G) The heterotopic neurons in the deep white matter, identified by their MAP2-immunoreactivity, have normal morphology and immunophenotype. (H) The deep white matter harboring the heterotopic neurons is gliotic with numerous vimentin-positive reactive astrocytes. (A) 25×; (B,C,E,F) 100×; (D,G,H) 200×.