Epileptic Encephalopathy, Early Infantile, 7

A number sign (#) is used with this entry because early infantile epileptic encephalopathy-7 (EIEE7) 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).

Description

Early infantile epileptic encephalopathy-7 is an autosomal dominant seizure disorder characterized by infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities (Borgatti et al., 2004). EEG initially shows a burst suppression pattern and later evolves to multifocal epileptiform activity. Brain imaging may show 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 Weckhuysen et al., 2012).

Clinical Features

Dedek et al. (2003) reported a mother and son with atypical severe early-onset epilepsy. Both patients had a severe course characterized by drug-resistant seizures necessitating ACTH treatment. The son had onset of seizures on day 3 of life. EEG showed sharp waves and suppression burst patterns. He developed epileptic encephalopathy and delayed psychomotor development with hypotonia and dystonia. The mother recovered in infancy and had normal psychomotor development.

Borgatti et al. (2004) reported a family in which 4 members in 2 generations had BFNS1, confirmed by the finding of a heterozygous mutation in the KCNQ2 gene (602235.0007). Two patients had a phenotype consistent with typical BFNS, 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 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 postulated that the phenotypic variability could be due to the interplay of pathogenic mutations, modifier genes, and more subtle environmental factors. Borgatti et al. (2004) noted 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.

Bassi et al. (2005) reported a large Italian family in which 8 individuals had BFNS1. A ninth family member developed severe epilepsy associated with mild mental retardation and persistent neurologic problems in adult life; this phenotypic variability was considered by the authors to be consistent with the fact that 10 to 15% of BFNC individuals experience seizures later in life. Genetic analysis identified a heterozygous truncating mutation in the KCNQ2 gene (602235.0009) in all 9 members.

Weckhuysen et al. (2012) reported 8 unrelated patients with EIEE7 confirmed by genetic analysis. 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 EIEE7. All patients developed seizures, mainly tonic, in the early neonatal period (1 to 14 days). Ten patients were diagnosed clinically with Ohtahara syndrome (see 308350). EEG of most patients showed a suppression-burst pattern; 3 patients had hypsarrhythmia. All patients showed intellectual disability with moderate to profound psychomotor delay. Many patients 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.

Molecular Genetics

In a mother and son with atypical severe early-onset epilepsy, Dedek et al. (2003) identified a heterozygous KCNQ2 mutation (S247W; 602235.0008). The son developed early infantile epileptic encephalopathy and delayed psychomotor development with hypotonia and dystonia. The mother recovered in infancy and had normal psychomotor development. Dedek et al. (2003) emphasized that some KCNQ2 mutations may be associated with a more severe phenotype than is typical for BFNS1.

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. The findings indicated that KCNQ2 mutations can occur in a substantial proportion of patients with EIEE.

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 EIEE and onset of seizures in the first week of life. The mutations were found by whole-exome sequencing. The findings suggested that KCNQ2 mutations may be a common cause of this disorder. Functional studies of the variants were not performed.

By high-resolution melting analysis or whole-exome sequencing of 239 patients with EIEE, 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 1, 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.