A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-7 (DEE7) is caused by heterozygous mutation in the KCNQ2 gene (602235) on chromosome 20q13.

Mutation in the KCNQ2 gene can also cause benign familial neonatal seizures-1 (BFNS1; 121200).

Developmental and epileptic encephalopathy-7 (DEE7) is a neurologic disorder characterized by the onset of refractory seizures in early infancy, often in the neonatal period. Affected individuals have resultant delayed neurologic development and persistent neurologic abnormalities. EEG initially shows a burst suppression pattern, consistent with a clinical diagnosis of Ohtahara syndrome, which may later evolve to multifocal epileptiform activity. Brain imaging in some patients shows lesions in the basal ganglia. Seizures usually remit by age 3 or 4 years, with improvement of EEG abnormalities and possibly brain imaging abnormalities, but the severe neurologic deficits persist (summary by Borgatti et al., 2004 and Weckhuysen et al., 2012).

Dedek et al. (2003) reported a mother and son with early-onset epilepsy with different outcomes. The son had onset of seizures on day 3 of life and the mother at age 1 month. Both patients had a severe course characterized by drug-resistant seizures necessitating ACTH treatment. EEG studies in the son showed sharp waves and suppression burst patterns. He had epileptic encephalopathy and delayed psychomotor development with hypotonia and dystonia. In contrast, the mother had remission of her seizures in infancy and subsequently showed normal psychomotor development. Genetic analysis identified a heterozygous KCNQ2 mutation (S247W; 602235.0008) in both patients. The report emphasized the phenotypic variability associated with mutations in the KCNQ2 gene.

Borgatti et al. (2004) reported a family in which 4 members in 2 generations had a heterozygous mutation in the KCNQ2 gene (602235.0007). Two patients had a phenotype consistent with typical benign familial neonatal seizures, whereas the other 2 had an atypical severe phenotype. After apparent resolution of BFNS at day 8 of life, the proband developed frequent right-sided tonic seizures in clusters (more than 60 per day) that were resistant to medication. At age 4 months, she developed polymorphic seizures which persisted to age 7 years, at the writing of the report. She also had severe mental retardation without language capability and spastic tetraparesis, consistent with an epileptic encephalopathy. The proband's mother and younger sister had isolated BFNS only, which resolved without sequelae. The proband's maternal aunt had BFNS and drug-resistant seizures until age 5 years. As an adult, she showed moderate mental retardation, mild dysmetria and ataxia, and nystagmus. Borgatti et al. (2004) noted that some patients with KCNQ2 mutations may experience seizures later in life or a different set of epileptic subtypes that are sometimes associated with severe neurologic and intellectual impairment. Overall, the clinical, genetic, and functional data did not provide a definitive explanation for the wide range of phenotypic variability observed in the family, therefore preventing genotype-phenotype correlations. The authors noted that the phenotypic variability could be due to the interplay of pathogenic mutations, modifier genes, and more subtle environmental factors, but thought that the complex phenotype and intrafamilial variability in this family was caused by a single mutation and referred to the report by Dedek et al. (2003) of a similar atypical BFNS phenotype.

Weckhuysen et al. (2012) reported 8 unrelated patients with neonatal epileptic encephalopathy. All patients had onset of seizures in the first week of life, and 2 mothers retrospectively noted intrauterine jerking during the last 2 months of pregnancy. At onset, all patients had multiple daily tonic seizures with motor and autonomic features that were resistant to treatment. Thereafter, seizure frequency decreased between 9 months and 4 years, and most became seizure-free. One patient still had frequent seizures at age 5.5 years, and another had recurrence of seizures at age 8 years after being seizure-free for 7 years. Seven patients were profoundly mentally impaired and had axial hypotonia and/or spastic quadriplegia. One patient had a slightly milder phenotype, but still showed psychomotor impairment. Brain imaging of patients showed variable T1- and T2-weighted hyperintensities in the basal ganglia and sometimes in the thalamus. In some cases, these lesions became less apparent with age. The EEG initially showed burst suppression patterns and later showed multiform epileptiform abnormalities. One of the severely affected children had a father who was mosaic for the KCNQ2 mutation (R213Q; 602235.0012); the father had benign neonatal seizures, normal intellect at age 35 years, and a history of mild myokymia.

Kato et al. (2013) reported the clinical features of 12 unrelated patients with early-onset epileptic encephalopathy. All patients developed seizures, mainly tonic, in the early neonatal period (1 to 14 days). EEG of most patients showed a suppression-burst pattern; 3 patients had hypsarrhythmia. Ten patients were diagnosed clinically with Ohtahara syndrome. All patients showed impaired intellectual development with moderate to profound psychomotor delay, and many had spastic quadriplegia. Six patients had abnormal brain MRI, with hyperintensities in the globus pallidus and abnormal myelination. Most patients achieved remission of seizures with anticonvulsant medications, particularly those that block voltage-gated sodium channels, although the overall neurologic prognosis was poor.

The transmission pattern of DEE7 in the family reported by Dedek et al. (2003) was consistent with autosomal dominant inheritance with variable expressivity.

The heterozygous mutations in the KCNQ2 gene that were identified in patients with DEE7 by Weckhuysen et al. (2012) occurred de novo.

In a boy with DEE7, Dedek et al. (2003) identified a heterozygous missense mutation in the KCNQ2 gene (S247W; 602235.0008). The mutation was inherited from his mother, who had a milder phenotype with resolution of seizures in infancy and subsequent normal development. Functional expression studies showed that the S247W mutation reduced channel currents by more than 50% in homomeric KCNQ2 channels. Dedek et al. (2003) emphasized that some KCNQ2 mutations may be associated with a more severe phenotype than is typical for BFNS.

Weckhuysen et al. (2012) identified 7 different heterozygous mutations in the KCNQ2 gene (see, e.g., 602235.0012-602235.0014) in 8 (10%) of 80 patients with neonatal or early infantile seizures and associated psychomotor retardation. The mutations arose de novo in 7 cases; in 1 case, a severely affected patient inherited the mutation from her father, who had a milder phenotype and was mosaic for the mutation.

Saitsu et al. (2012) identified 3 different de novo missense mutations in the KCNQ2 gene (see, e.g., A265V; 602235.0015) in 3 of 12 probands with DEE and onset of seizures in the first week of life. The phenotype was consistent with a clinical diagnosis of Ohtahara syndrome. The mutations were found by whole-exome sequencing. Functional studies of the variants were not performed.

By high-resolution melting analysis or whole-exome sequencing of 239 patients with early-onset epileptic encephalopathy, Kato et al. (2013) found that 12 patients carried a total of 10 heterozygous missense mutations in the KCNQ2 gene. The mutations occurred de novo in all patients except one, who inherited the mutation from her mildly affected mother who was somatic mosaic for the mutation. Several of the mutations had previously been reported (see, e.g., A265V, 602235.0015), but functional studies were not performed.