A number sign (#) is used with this entry because of evidence that generalized epilepsy with febrile seizures plus-9 (GEFSP9) is caused by heterozygous mutation in the STX1B gene (601485) on chromosome 16p11.

Generalized epilepsy with febrile seizures plus-9 is an autosomal dominant neurologic disorder characterized by onset of febrile and/or afebrile seizures in early childhood, usually before age 3 years. Seizure types are variable and include generalized tonic-clonic, atonic, myoclonic, complex partial, and absence. Most patients have remission of seizures later in childhood with no residual neurologic deficits, but rare patients may show mild developmental delay or mild intellectual disabilities (summary by Schubert et al., 2014).

For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233.

Lerche et al. (2001) reported a large 5-generation German family in which 18 individuals experienced early-onset febrile and/or afebrile seizures, with great variability in presentation and course. Schubert et al. (2014) provided follow-up of the family reported by Lerche et al. (2001), noting that several family members with a slightly atypical phenotype who were thought to be affected did not carry the pathogenic STX1B mutation. Six individuals had the core phenotype and carried the mutation. Five patients had onset of both febrile and afebrile seizures around 2 years of age; 1 patient had only afebrile seizures. Seizure types included generalized tonic-clonic, tonic, atonic, and absence. All patients became seizure-free later in childhood. Two individuals with seizures had been diagnosed with Asperger syndrome, but neurologic and cognitive development was normal in all other patients.

Weber et al. (2008) reported a large 4-generation German family in which 8 individuals had various forms of febrile and/or afebrile seizures. Six patients had several febrile seizures between the ages of 10 months and 4 years, 5 of whom also developed afebrile seizures, either generalized tonic-clonic, atonic, or complex partial. Two patients only had afebrile atonic and generalized tonic-clonic seizures, respectively. EEG during early childhood showed multifocal and generalized discharges, but these abnormalities tended to disappear between ages 2 and 6 years, except in 1 patient whose EEG was still abnormal at age 15. All patients had a good response to treatment, and most were able to discontinue treatment later in childhood without recurrence of seizures. Neurologic examination was unremarkable in all patients, although 2 had reduced intelligence and concentration deficit. Weber et al. (2008) noted that the phenotype was similar to benign familial infantile seizures, but that there were some distinctive features, including later onset of seizures after 12 months of age and a high rate of febrile seizures. In a follow-up of the family reported by Weber et al. (2008), Schubert et al. (2014) noted that all affected individuals were seizure-free.

Schubert et al. (2014) reported a Dutch girl with GEFSP9 who developed seizures at age 10 months. She had normal psychomotor development at age 16 months.

Clinical Variability

Schubert et al. (2014) reported 3 unrelated patients with a more severe phenotype associated with mutation in or deletion of the STX1B gene. An adult Swiss patient developed generalized tonic-clonic seizures at age 3.5 years. He had speech delay and later showed moderate intellectual disability (IQ of 48), ataxia, and cerebellar atrophy. The seizures were highly pharmacoresistant. A German girl developed febrile seizures at age 13 months, severe and frequent myoclonic-astatic seizures at age 19 months, and afebrile seizures associated with status epilepticus at age 3 years. She showed global developmental delay, mild intellectual disability, and mild ataxia. An unrelated German girl, who had a deletion encompassing the STX1B gene, developed seizures consistent with myoclonic-astatic epilepsy at age 13 months after showing mild global developmental delay. At age 2 years, she had hypotonia and was developmentally delayed.

The transmission pattern of GEFSP9 in the families reported by Lerche et al. (2001) and Weber et al. (2008) was consistent with autosomal dominant inheritance.

By linkage analysis of a large German family with early-onset febrile and afebrile seizures, Weber et al. (2008) found evidence suggestive of linkage to chromosome 16p11.2-q12.1 (maximum lod score of 2.1 at marker D16S411).

In affected members of the families with GEFSP9 reported by Lerche et al. (2001) and Weber et al. (2008), Schubert et al. (2014) identified different heterozygous truncating mutations in the STX1B gene (601485.0001 and 601485.0002, respectively). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Sequencing of the GEFSP9 gene in 3 additional cohorts of patients with seizures identified a mutation in 1 of 299 probands with febrile seizures or epileptic encephalopathies; in 1 of 81 adults with various forms of epilepsy and intellectual disability; and in 1 of 68 patients with epileptic encephalopathies. A de novo microdeletion encompassing the STX1B gene was found in a further patient with myoclonic-astatic epilepsy. Schubert et al. (2014) noted the wide phenotypic spectrum of epilepsy associated with STX1B mutations, ranging from incomplete penetrance without symptoms to simple febrile seizures to severe epileptic encephalopathies. The findings implicated the STX1B gene and the presynaptic release machinery in fever-associated epilepsy syndromes.

Schubert et al. (2014) found that morpholino knockout of the stx1b gene in zebrafish resulted in abnormal episodic behavior, including repetitive fin fluttering, increased orofacial movements, and myoclonus-like jerks, as well as abnormal spontaneous epileptiform brain activity with polyspiking discharges and high-frequency oscillations. Elevation of temperature increased the occurrence of epileptiform events, specifically high-frequency oscillations.