Epileptic Encephalopathy, Early Infantile, 4

A number sign (#) is used with this entry because early infantile epileptic encephalopathy-4 (EIEE4) is caused by heterozygous mutation in the STXBP1 gene (602926) on chromosome 9q34.1.

For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).

Clinical Features

Tohyama et al. (2008) reported a Japanese infant girl who developed tonic seizures, tremulous arm movements, and oral automatisms at 45 days of age. Her dizygotic twin was unaffected; the pregnancy resulted from in vivo fertilization. The proband continued to have seizures with increased frequency, spastic quadriplegia, and poor visual attention. EEG showed a suppression-burst pattern and hypsarrhythmia, consistent with EIEE. She had severely delayed psychomotor development with no language. Brain MRI showed diffuse hypomyelination, cortical atrophy, and a thin corpus callosum.

Saitsu et al. (2008) reported 4 Japanese patients with EIEE. All had neonatal or infantile onset of tonic-clonic or tonic seizures, suppression-burst pattern on EEG, profound mental retardation, and MRI evidence of hypomyelination. Other features included hypsarrhythmia and spastic di- or quadriplegia. Major structural brain abnormalities were not observed.

Hamdan et al. (2009) reported 2 unrelated French Canadian patients with EIEE4. One patient was a 27-year-old woman who first developed partial complex seizures at age 6 weeks. The second patient was a 15-year-old girl who first developed partial complex seizures at 2 years, 9 months of age. Both patients had severe mental retardation, hypotonia, and tremor. Brain scan in both patients was normal. Hamdan et al. (2009) noted that the phenotypes of both patients were slightly different than that reported by Saitsu et al. (2008), with later onset of seizures and some response to antiepileptic medication. In addition, hypsarrhythmia was never observed.

Deprez et al. (2010) identified heterozygous truncating mutations in the STXBP1 gene in 6 (5.7%) of 106 patients with various types of early-onset epileptic encephalopathies. Variable seizures first occurred between 3 days and 4.5 months of life, and all patients subsequently had severe to profound mental retardation. Three patients developed hypsarrhythmia by 5 months of age, consistent with a clinical diagnosis of West syndrome. Four patients showed an initial favorable response to vigabatrin and became seizure-free later in childhood even without medication, but 2 had continued seizures despite treatment with antiepileptic medications. None of the patients had a burst-suppression pattern on EEG, as had been observed in the patients reported by Saitsu et al. (2008). Three patients were wheelchair-bound due to hypotonia or dyskinesias. Five patients had proven de novo mutations; parental DNA from the sixth patient was not available. Deprez et al. (2010) emphasized the phenotypic variability in the severity of the epilepsy, but noted that all patients had mental retardation, which suggested that neurodegeneration is an intrinsic property of the disorder.

Carvill et al. (2014) reported 3 unrelated patients with EIEE4. The patients had onset of seizures between 6 and 12 months of age, which the authors noted was later than other patients with this disorder. Seizure types included tonic-clonic, absence, atonic, myoclonic, focal dyscognitive, and status epilepticus. The seizures were fever-sensitive. Two patients showed developmental regression and had severe intellectual disability, whereas the third patient had learning difficulties. EEG in the patients with more severe outcomes showed multifocal discharges, whereas EEG in the patient with mild features was normal. One severely affected patient showed cerebral atrophy on brain MRI, and the other severely affected patient died at age 11 years.

Inheritance

Saitsu et al. (2011) noted that de novo mutations in the STXBP1 gene have been reported in patients with EIEE4, consistent with sporadic occurrence of the disorder. They reported a girl with EIEE4 confirmed by genetic analysis revealing a heterozygous truncating mutation in the STXBP1 gene that was inherited from her unaffected father, who was somatic mosaic for the mutation. Cloning of PCR products amplified with the paternal DNA samples extracted from his blood, saliva, buccal cells, and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, respectively. Although sperm was not tested, the father likely carried the mutation in the mosaic state in his germ cells. Saitsu et al. (2011) emphasized the importance of the finding for genetic counseling, as recurrence of the disorder in this family is possible.

Molecular Genetics

In a Japanese girl with early infantile epileptic encephalopathy (Tohyama et al., 2008), Saitsu et al. (2008) identified a de novo heterozygous microdeletion at chromosome 9q33.3-q34.11 including the STXBP1 gene. Screening of this gene in 13 additional unrelated patients with a similar phenotype identified 4 different heterozygous mutations in the STXBP1 gene (602926.0001-602926.0004) in 4 patients. In 3 of the patients the mutation was shown to be de novo. Saitsu et al. (2008) concluded that haploinsufficiency of STXBP1 results in impaired synaptic vesicle release and the phenotype of EIEE.

In 2 unrelated French Canadian patients with severe mental retardation and epilepsy, Hamdan et al. (2009) identified respective de novo heterozygous truncating mutations in the STXBP1 gene (602926.0005 and 602926.0006). The patients were ascertained from a larger group of 95 patients with idiopathic mental retardation.

In an 11-year-old boy with EIEE4 who was negative for mutations in the SCN1A gene (182389), Carvill et al. (2014) identified a de novo heterozygous missense mutation in the STXBP1 gene (E283K; 602926.0008). The mutation was found by whole-exome sequencing. Targeted resequencing of 67 patients with a similar disorder identified 2 additional probands with de novo heterozygous missense mutations in the STXBP1 gene. Functional studies of the variants were not performed.

Cytogenetics

Saitsu et al. (2010) reported that the microdeletion in the patient previously reported by Tohyama et al. (2008) and Saitsu et al. (2008) was 2.25 Mb long and encompassed both the STXBP1 and SPTAN1 (182810) genes. This patient had hypomyelination at 12 months, but showed progression of myelination at age 4 years. Saitsu et al. (2010) hypothesized that this patient's phenotype was due more to haploinsufficiency of STXBP1, but that haploinsufficiency of SPTAN1 may have had some effect on myelination, because dominant-negative SPTAN1 mutations were found to cause severe hypomyelination and widespread brain atrophy (see EIEE5, 613447).

Using array CGH, Saitsu et al. (2012) identified 2 different de novo heterozygous deletions involving the STXBP1 gene in 2 (7.1%) of 28 patients with cryptogenic early-onset epileptic encephalopathy. One was a 4.6-kb deletion involving only exon 4 of the STXBP1 gene, and the other was a 2.85-Mb deletion involving 70 genes, including both STXBP1 and SPTAN1. The patient with the smaller deletion developed tonic and myoclonic seizures on day 32 of life. EEG showed a suppression-burst pattern, and brain MRI was normal. Seizure frequency was reduced with high-dose phenobarbital. The patient with the larger deletion had multiple anomalies, including low birth weight, cleft lip and palate, ventricular septal defect, small penis, thin corpus callosum, and small cerebellum. Seizures with suppression-burst pattern on EEG developed around age 1 month. At 19 months, the child showed spastic quadriplegia and profound intellectual disability. Analysis of the breakpoints in both patients suggested that nonhomologous recombination led to the rearrangements.