A number sign (#) is used with this entry because developmental and epileptic encephalopathy-14 (DEE14) is caused by heterozygous mutation in the KCNT1 gene (608167) on chromosome 9q34.

Developmental and epileptic encephalopathy-14 (DEE14) is a severe neurologic disorder characterized by onset in the first 6 months of life of refractory focal seizures and arrest of psychomotor development. Ictal EEG shows discharges that arise randomly from various areas of both hemispheres and migrate from one brain region to another. The disorder presents as 'malignant migrating partial seizures of infancy' (MMPSI), a clinical designation (summary by Barcia et al., 2012).

For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Coppola et al. (1995) first delineated MMPSI as a clinical entity. Fourteen infants presented at a mean age of 3 months with nearly continuous multifocal seizures involving both cerebral hemispheres. The seizures usually started as focal motor seizures and often showed secondary generalization. Autonomic manifestations, such as apnea, cyanosis, or flushing, were common. The seizures were refractory and became very frequent over the first few months, becoming almost continuous. EEG showed discharges randomly involving multiple independent sites and moving from one cortical area to another. The pattern tended to consist of rhythmic alpha or theta activity that spread to involve an increasing area of the cortical surface. The patients showed developmental regression and became quadriplegic with severe axial hypotonia. Three patients died at ages 7 months, 7 years, and 8 years. Neuropathologic examination of the brain in 2 cases showed severe hippocampal neuronal loss and accompanying gliosis. There was no familial recurrence of a similar disorder, although some had a family history of seizures. In the 2 patients in whom seizure control was obtained, motor and cognitive abilities were partially recovered.

Wilmshurst et al. (2000) reported 2 unrelated infants with MMPSI. The first was a girl who presented at age 3 weeks with eye opening, staring, eyelid flickering, and twitching of the limbs. The seizures were refractory to treatment. From 8 weeks on, she had multiple types of seizures often with secondary generalization. The seizures continued to be frequent and she remained hospitalized until age 6 months. She showed no developmental progress since the onset of seizures, had truncal hypotonia and limb spasticity, and was drowsy and unresponsive. Extensive laboratory workup found no etiology for the seizures. EEG reflected the escalation of seizure activity, with great variability in the site of onset, multiple seizures arising from the same region, and spreading of the seizures to adjacent brain regions. She died of pneumonia at age 9 months. The second patient was a boy who showed normal development until the onset of refractory seizures at age 3 months. He had multiple seizure types, including facial twitching, eye deviation, limb jerking, and secondary generalization. He was hypotonic with hyperreflexia and clonus. EEG showed multifocal epileptogenic foci on a slow background. He died at age 12 months. Wilmshurst et al. (2000) emphasized the extremely poor prognosis of patients with this form of infantile-onset seizures.

Marsh et al. (2005) retrospectively reviewed the clinical course of 6 unrelated infants with early-onset intractable seizures that alternated between the cerebral hemispheres and were consistent with MMPSI. Seizures often occurred multiple times a day. After seizure onset, the patients showed a plateau or decline in psychomotor development, and about half showed progressive microcephaly. Interictal EEG varied from normal to slow, with multifocal sharp waves. The onset of seizures in 4 patients had evolving rhythmic sharp activity in the theta to alpha frequency range. Ictal onset varied from side to side and within each hemisphere; many showed a migratory pattern. Five patients were available for follow-up. Of these, only 1 showed profound psychomotor retardation, whereas the others were less severely disabled. One 6-year-old child could walk and talk and showed learning disabilities. These findings suggested that the outcome of the disorder may not be as poor as suggested by the original report of Coppola et al. (1995).

Lee et al. (2012) reported a Korean boy who presented at age 2 months with refractory multifocal partial seizures. The seizures occurred in clusters up to 10 times a day. EEG showed migrating multifocal epileptiform activity, consistent with a clinical diagnosis of MMPSI. At age 9 months he had epileptic spasms, and EEG showed hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. He developed progressive microcephaly and showed severe neurologic impairment with poor visual following and generalized hypotonia. The finding suggested that both MMPSI and West syndrome represent a phenotypic continuum of infantile epileptic encephalopathy and probably share a common pathophysiology relating to hyperexcitability.

Barcia et al. (2012) reported 6 unrelated patients with MMPSI due to heterozygous mutations in the KCNT1 gene (614959.0001-614959.0004). All patients had onset of refractory focal seizures and arrest of psychomotor development in the first 2 months of life. The seizures showed secondary generalization in some patients. Brain MRI of most patients showed delayed myelination, cortical atrophy, and thin corpus callosum. Other features included poor or no eye contact, lack of speech and walking, and microcephaly. The oldest patients were 10 years old at the time of the study and showed profound psychomotor retardation.

Vanderver et al. (2014) reported a child with leukoencephalopathy and severe epilepsy. He presented at age 1 month with refractory myoclonic seizures that progressed to several different seizure types, including status epilepticus. He had microcephaly and encephalopathic encephalopathy, with severe developmental stagnation and abnormal involuntary movements. Brain imaging showed severely delayed myelination, and EEG showed background slowing with superimposed multifocal interictal sharp discharges and occasional periods of burst-suppression.

Ishii et al. (2013) reported 2 unrelated girls with DEE14 presenting as malignant migrating partial seizures in infancy. Both girls had onset of focal seizures at 2 months of age, following apparently normal development. The seizures occurred 20 to 30 times a day and were refractory to treatment. Interictal EEGs showed asynchronous high-voltage slow activities with multifocal spikes. Ictal EEGs demonstrated either focal or multifocal seizure activity that often migrated to other areas. Both patients had hypotonia and severely delayed psychomotor development with lack of head control and lack of visual following.

The diagnostic criteria for MMPSI suggested by Coppola et al. (1995) included normal development before seizure onset, onset before age 6 months, migrating focal motor seizures at onset, multifocal seizures becoming intractable and treatment-resistant, profound psychomotor delay, and no identifiable etiology.

All patients with DEE14 reported by Barcia et al. (2012) had sporadic occurrence of the disorder due to de novo heterozygous mutations in the KCNT1 gene.

In 6 (50%) of 12 unrelated patients with sporadic occurrence of developmental and epileptic encephalopathy-14 manifest clinically as MMPSI, Barcia et al. (2012) identified 4 different de novo heterozygous mutations in the KCNT1 gene (608167.0001-608167.0004). The first 2 mutations were identified by exome sequencing. Expression of 2 of the corresponding rat mutations in Xenopus oocytes resulted in Kcnt1-generated currents that resembled wildtype in terms of voltage dependence and kinetic behavior but had 2- to 3-fold higher amplitude compared to wildtype, consistent with a gain of function. The mutations were shown to cause constitutive activation of the Kcnt1 channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C (see, e.g., PRKCA, 176960) activation. Although mutations in the SCN1A gene (182389) have rarely been associated with the MMPSI phenotype (see DEE6, 607208), none of the 12 patients reported by Barcia et al. (2012) had mutations in the SCN1A gene, suggesting that KCNT1 is a major disease-associated gene that is specific for the MMPSI phenotype. In addition, 6 patients with this phenotype reported by Barcia et al. (2012) did not have KCNT1 mutations, indicating further genetic heterogeneity for MMPSI.

In a child with DEE14 and severely delayed myelination, Vanderver et al. (2014) identified a de novo heterozygous mutation in the KCNT1 gene (F932I; 608167.0009). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.

In 2 unrelated girls with DEE14 manifest as malignant partial migrating seizures in infancy, Ishii et al. (2013) identified the same de novo heterozygous mutation in the KCNT1 gene (G288S; 608167.0010).