A case of severe progressive early-onset epileptic encephalopathy: unique GABAergic interneuron distribution and imaging.

Early-onset epileptic encephalopathies include various diseases such as early-infantile epileptic encephalopathy with suppression burst. We experimentally investigated the unique clinicopathological features of a 28-month-old girl with early-onset epileptic encephalopathy. Her initial symptom was intractable epilepsy with a suppression-burst pattern of electroencephalography (EEG) from 7 days of age. The suppression-burst pattern was novel, appearing during sleep, but disappearing upon waking and after becoming 2 months old. The EEG showed multifocal spikes and altered with age. Her seizures demonstrated various clinical features and continued until death. She did not show any developmental features, including no social smiling or head control. Head MRI revealed progressive atrophy of the cerebral cortex and white matter after 1 month of age. (123)IMZ-SPECT demonstrated hypo-perfusion of the cerebral cortex, but normo-perfusion of the diencephalon and cerebellum. Such imaging information indicated GABA-A receptor dysfunction of the cerebral cortex. The genetic analyses of major neonatal epilepsies showed no mutation. The neuropathology revealed atrophy and severe edema of the cerebral cortex and white matter. GAD-immunohistochemistry exhibited imbalanced distribution of GABAergic interneurons between the striatum and cerebral cortex. The results were similar to those of focal cortical dysplasia with transmantle sign and X-linked lissencephaly with ARX mutation. We performed various metabolic examinations, detailed pathological investigations and genetic analyses, but could not identify the cause. To our knowledge, her clinical and pathological courses have never been described in the literature.

Neuroradiologic features of CASK mutations.

Mutations of the CASK gene are associated with X-linked mental retardation with microcephaly and disproportionate brain stem and cerebellar hypoplasia in females. The areas of the cerebrum, corpus callosum, pons, midbrain, and cerebellar vermis and hemisphere and a ratio of cerebrum/corpus callosum areas were measured in 5 female patients with CASK mutations, 67 female controls, and 5 patients with pontine hypoplasia. MR imaging in patients with CASK mutations revealed a normal size of the corpus callosum and a low ratio of the cerebrum/corpus callosum with a reduced area of the cerebrum, pons, midbrain, and cerebellar vermis and hemispheres. The 5 patients with pontine hypoplasia showed thinning of the corpus callosum and a high ratio of the cerebrum/corpus callosum, irrespective of the size of the cerebrum. The normal size of the corpus callosum, which gives an impression of callosal thickening at first glance, may be an imaging clue to detect patients with CASK mutations.