Developmental and Epileptic Encephalopathy 4 via the STXBP1 Gene

STXBP1-related developmental and epileptic encephalopathy 4 (DEE4, also known as STXBP1 encephalopathy, or early infantile epileptic encephalopathy 4) is an early-onset disorder characterized by developmental delay, intellectual disability, and seizures. All affected individuals have developmental delay and moderate to severe intellectual disability. Seizures, once the defining phenotype of this disease, are not recognized in approximately 6% of affected individuals (Hamdan et al. 2011. PubMed ID: 21364700; Stamberger et al. 2016. PubMed ID: 26865513; Gburek-Augustat et al. 2016. PubMed ID: 27184330). Additional features described in less than 50% of patients include autistic behavior, movement disorder (primarily ataxia), hypotonia, and various MRI abnormalities (reduced white matter volume, dilated ventricles, thin corpus callosum, and cerebral atrophy) (Khaikin et al. 1993. PubMed ID: 27905812).

The type of seizures associated with DEE4 are varied and include infantile spasms, generalized tonic-clonic, generalized clonic, generalized tonic, myoclonic, atonic, focal, and absence seizures. In the majority of patients, seizure-onset is within the first months of life; however, in rare cases onset may be up to 13 years of age (Khaikin et al. 1993. PubMed ID: 27905812). Most patients experience more than one seizure type in their lifetime.

DDEE4 has been associated with several different seizure syndromes as defined by the International League Against Epilepsy (Scheffer et al. 2017. PubMed ID: 28276062). The first documented cases of STXBP1-related disease were diagnosed with Ohtahara syndrome, with generalized tonic seizures and a characteristic suppression-burst pattern on EEGs (Saitsu et al. 2008. PubMed ID: 18469812). However, at onset, one study found that the most common seizure phenotype is early-onset epilepsy and encephalopathy (53%) followed by Ohtahara syndrome (21%; Stamberger et al. 2016. PubMed ID: 26865513). Several other phenotypes have been associated with STXBP1 including West syndrome, Lennox-Gestaut syndrome, early myoclonic epileptic encephalopathy, Dravet syndrome, and Rett syndrome phenotype. Additionally, it is common for Ohtahara syndrome to progress into West syndrome and less frequently Lennox-Gestaut syndrome (Ohtahara and Yamatogi 2006. PubMed ID: 16829045; Saitsu et al. 2008. PubMed ID: 18469812; Stamberger et al. 2016. PubMed ID: 26865513).

STXBP1-related developmental and epileptic encephalopathy is rare. However, in one Danish study it has been estimated to be among the five most common causes of epilepsy with intellectual disability (prevalence of 1:92,000) (Stamberger et al. 2016. PubMed ID: 26865513). Due to the broad phenotypic spectrum of DEE4, all genes associated with early infantile epileptic encephalopathy should be considered in the differential diagnosis, including several with direct treatment implications (Khaikin et al. 1993. PubMed ID: 27905812). Therefore, if possible, testing for STXBP1 variants by way of a multi-gene panel is strongly encouraged.  

A diagnosis of DEE4 can provide important prognostic information and guide pharmacological therapy. This disorder results in profound disability and reduced life expectancy. Conventional antiepileptic drugs used in combinations have proven effective in reducing seizure activity in some individuals. However, currently treatment is limited to managing symptoms, and 25% of cases are refractory to medication (Khaikin et al. 1993. PubMed ID: 27905812). Importantly, research on STXBP1 precision therapies are ongoing (Stamberger et al. 2017. PubMed ID: 28971703). 

STXBP1-related developmental and epileptic encephalopathy 4 is autosomal dominant and apparently fully penetrant. To date, nearly all cases have involved de novo variants, which are believed to result in loss-of-function and haploinsufficiency. Variants are of all types: missense, nonsense, splice site, small insertions/deletions and large deletions. They are evenly spread across the coding sequence of the gene, with the exception of one alternatively spliced exon near the 3’ end of the gene. Natural variation, as represented in the gnomAD database, suggests that STXBP1 is modestly intolerant to missense variation and strongly intolerant to premature termination (loss-of-function).  

STXBP1 (syntaxin-binding protein) is a neuronally expressed soluble protein that localizes to pre-synaptic terminals. There, it binds to syntaxin and the SNARE complex to facilitate synaptic vesicle fusion (Shen et al. 2007. PubMed ID: 17218264; Toonen and Verhage. 2007. PubMed ID: 17956762). The precise biochemical functions of this protein have been worked out in extensive studies involving model organisms including yeast, flies, nematodes, and mice. In all multicellular organisms, homozygous nulls result in a complete loss of neurotransmitter secretion, neuronal apoptosis, and lethality (Toonen and Verhage. 2007. PubMed ID: 17956762).

The clinical sensitivity of sequencing the STXBP1 gene will depend on the patient’s phenotype. In one study, a causative variant was identified in ~35% of patients clinically diagnosed with Ohtahara syndrome (Ottman et al. 2010.PubMed ID: 20100225). This is expected to be the upper limit of the clinical sensitivity for this test.

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of STXBP1 plus 10 bases of flanking noncoding DNA along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.