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STXBP1 Encephalopathy with Epilepsy

Synonyms: Early-Infantile Epileptic Encephalopathy 4 (EIEE4), STXBP1 Epileptic Encephalopathy

, BSc and , MD, PhD, FCCMG.

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Estimated reading time: 18 minutes

Summary

Clinical characteristics.

STXBP1 encephalopathy with epilepsy is characterized by early-onset encephalopathy with epilepsy (i.e., moderate to severe intellectual disability, refractory seizures, and ongoing epileptiform activity). The median age of onset of seizures is six weeks (range 1 day to 13 years). Seizure types can include infantile spasms; generalized tonic-clonic, clonic, or tonic seizures; and myoclonic, focal, atonic, and absence seizures. Epilepsy syndromes can include Ohtahara syndrome, West syndrome, Lennox-Gaustaut syndrome, and Dravet syndrome (not SCN1A-related), classic Rett syndrome (not MECP2-related), and atypical Rett syndrome (not CDKL5-related). The EEG is characterized by focal epileptic activity, burst suppression, hypsarrhythmia, or generalized spike-and-slow waves. Other findings can include abnormal tone, movement disorders (especially ataxia and dystonia), and behavior disorders (including autism spectrum disorder). Feeding difficulties are common.

Diagnosis/testing.

The diagnosis is established in a proband by identification of a heterozygous intragenic pathogenic variant in STXBP1 or a contiguous gene deletion that includes STXBP1 and adjacent genes on molecular genetic testing.

Management.

Treatment of manifestations: Developmental delay, cognitive dysfunction, and intellectual disability are managed in the usual manner. The most commonly used antiepileptic drugs (AEDs) are phenobarbital, valproic acid, and vigabatrin; an estimated 20% of individuals require more than one AED and approximately 25% are refractory to AED therapy. Severe dystonia, dyskinesia, and choreoathetosis can be treated with monoamine depleters or dopaminergic agents. Behavior disorders and feeding difficulties are managed symptomatically in the usual manner.

Surveillance: Neuropsychological assessment and EEG are performed as needed.

Genetic counseling.

STXBP1 encephalopathy with epilepsy is inherited in an autosomal dominant manner. To date, most probands represent simplex cases (i.e., a single occurrence in a family) and have the disorder as a result of a de novo STXBP1 pathogenic variant. Individuals with STXBP1 encephalopathy with epilepsy are not known to reproduce. Once the STXBP1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Diagnosis

No formal diagnostic criteria for STXBP1 encephalopathy with epilepsy have been published.

Suggestive Findings

STXBP1 encephalopathy with epilepsy should be considered in individuals with early-onset encephalopathy with epilepsy (i.e., developmental delay, cognitive dysfunction, or intellectual disability associated with refractory seizures, and ongoing epileptiform activity), particularly those with the following epilepsy features, seizure types, and/or epilepsy syndromes.

Epilepsy features

  • Median age of onset six weeks (range 1 day to 13 years)
  • EEG characterized by focal epileptic activity, burst suppression, hypsarrhythmia, or generalized spike-and-slow waves

Seizure types

  • Infantile spasms
  • Generalized tonic-clonic, clonic, or tonic seizures
  • Myoclonic seizures
  • Atonic seizures
  • Absence seizures
  • Focal seizures

Epilepsy syndromes

  • Ohtahara syndrome
  • West syndrome
  • Early myoclonic epileptic encephalopathy
  • Lennox-Gaustaut syndrome
  • Dravet syndrome not caused by mutation of SCN1A
  • Rett syndrome phenotype not caused by mutation of MECP2 or CDKL5

Other features

  • Moderate to profound intellectual disability
  • Behavior disorders, including autism spectrum disorder
  • Abnormal tone: spasticity, hypotonia
  • Movement disorders including ataxia, dystonia, dyskinesia, tremor, or choreoathetosis

Establishing the Diagnosis

The diagnosis of STXBP1 encephalopathy with epilepsy is established in a proband with suggestive findings and identification by molecular genetic testing of a heterozygous intragenic pathogenic variant in STXBP1 or a contiguous gene deletion that includes STXBP1 and adjacent genes (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) or genomic testing (chromosomal microarray analysis [CMA] or comprehensive genomic sequencing).

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotypes of many genetic epileptic encephalopathies overlap, most children with STXBP1 encephalopathy with epilepsy are diagnosed by the following recommended testing (a multigene panel or CMA) or testing to be considered (comprehensive genomic sequencing).

Recommended Testing

A multigene panel that includes STXBP1 and other genes of interest (see Differential Diagnosis) should be considered. For STXBP1 encephalopathy, a panel that includes gene-targeted deletion/duplication analysis is recommended to detect the 5% of STXBP1 pathogenic variants due to intragenic deletions.

Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. If STXBP1 encephalopathy is suspected, testing that includes sequencing as well as gene-targeted deletion/duplication analysis is recommended to detect the 5% of STXBP1 variants that are due to intragenic deletions or duplications.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Chromosomal microarray analysis (CMA). A contiguous gene deletion (≤4 MB) that encompasses STXBP1 along with as many as 92 contiguous genes has been reported in 20 affected individuals [Saitsu et al 2008, Mignot et al 2011, Campbell et al 2012, Saitsu et al 2012, Mastrangelo et al 2013, Barcia et al 2014, Matsumoto et al 2014, Di Meglio et al 2015, Ehret et al 2015, Nicita et al 2015, Nambot et al 2016, Stamberger et al 2016].

Testing to Consider

Comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if the phenotype is indistinguishable from other inherited disorders (or the phenotype alone is insufficient to support gene-targeted testing).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: Single-gene testing (sequence analysis of STXBP1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. Because the phenotype of STXBP1 encephalopathy with epilepsy overlaps with that of other genetic epileptic encephalopathies, the recommended testing and testing to consider are typically used in lieu of single-gene testing.

Table 1.

Molecular Genetic Testing Used in STXBP1 Encephalopathy with Epilepsy

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
STXBP1Sequence analysis 383%
Gene-targeted deletion/duplication analysis 45%
CMA 512%
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. Cases involving large deletions encompassing STXBP1 as well as other genes were excluded.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted array CGH (a gene-targeted microarray designed to detect single-exon deletions or duplications).

5.

Deletion/duplication analysis (genomic approach) detects deletion of STXBP1 and other contiguous genes using a chromosomal microarray (CMA) that specifically includes this gene/chromosome segment.

Clinical Characteristics

Clinical Description

Since the original description of STXBP1 encephalopathy with epilepsy in five individuals with Ohtahara syndrome [Saitsu et al 2008], approximately 200 affected individuals have been reported [Vatta et al 2012, Allen et al 2013, Tucker et al 2014, Ehret et al 2015, Kwong et al 2015, Dilena et al 2016, Guacci et al 2016, Helbig 2016, Marchese et al 2016]; see also Di Meglio et al [2015], Allen et al [2016], Nambot et al [2016], Yamamoto et al [2016], Lopes et al [2016] and references therein.

All affected individuals have developmental delay, cognitive dysfunction, or intellectual disability. The majority of affected individuals have presented with seizures.

Developmental delay, cognitive dysfunction, or intellectual disability, present in all individuals with STXBP1 encephalopathy with epilepsy, range from moderate to severe in more than 90% of individuals.

Seizures are the second most common clinical feature in STXBP1 encephalopathy with epilepsy. Although the majority of affected individuals presented with seizures, ten (6%) had no history of seizures [Hamdan et al 2011, Rauch et al 2012, Gburek-Augustat et al 2016, Stamberger et al 2016].

Onset of seizures ranges from ages six hours to 13 years [Milh et al 2011, Di Meglio et al 2015]. About half of affected children had seizures in the neonatal period. Approximately 40% had seizures between ages one month and 12 months. In fewer than 10% of affected individuals, seizure onset was after age one year.

Seizure types include infantile spasms and generalized tonic-clonic, generalized clonic, generalized tonic, myoclonic, atonic, and absence seizures. More than 60% of affected individuals had more than one seizure type during their lifetime.

Focal seizures were reported in about 10% of affected individuals.

Epilepsy syndromes

Electroencephalography (EEG) abnormalities were reported in the majority of affected individuals.

The two most common EEG abnormalities were burst suppression pattern (42 affected individuals) and hypsarrhythmia (37 affected individuals) [Saitsu et al 2012, Allen et al 2013, Kim et al 2013, Di Meglio et al 2015, Sampaio et al 2015, Allen et al 2016, Guacci et al 2016]; see also Yamamoto et al [2016] and references therein.

Other EEG abnormalities included focal and multifocal discharges, spike-and-slow wave activity, poly-spike waves, theta and delta waves, paroxysmal activity, and low-amplitude fast rhythms. Background activity was frequently described as slow or poorly organized.

Brain magnetic resonance imaging (MRI) was reported in more than 75% of affected individuals. In about half of these individuals, brain MRI showed various abnormalities including diffuse cerebral atrophy, delayed myelination, or thinning of the corpus callosum.

Hypotonia or absence of head control was reported in fewer than 50% of affected individuals.

Movement disorders were observed in fewer than 50 affected individuals.

Ataxia, the most common movement disorder, was either isolated or in combination with other movement disorders including dyskinesia, dystonia, tremor, or choreoathetosis [Campbell et al 2012, Rauch et al 2012, Keogh et al 2015, Mercimek-Mahmutoglu et al 2015, Olson et al 2015, Romaniello et al 2015]; see also Di Meglio et al [2015] and references therein.

Dystonia, the second most common movement disorder, was present in fewer than ten individuals, sometimes occurring in combination with tremor, rigidity, or dyskinesia [Milh et al 2011, Rauch et al 2012, Barcia et al 2013, Di Meglio et al 2015, Keogh et al 2015, Kwong et al 2015, Sampaio et al 2015, Guacci et al 2016, Stamberger et al 2016].

Behavior disorders including autism spectrum disorder, autistic-like features, hyperactivity, or self-aggressive behavior were seen in fewer than 40 affected individuals. Autistic features were the most common behavior disorder [Campbell et al 2012, Allen et al 2013, Weckhuysen et al 2013, Boutry-Kryza et al 2015, Mercimek-Mahmutoglu et al 2015, Romaniello et al 2015, Allen et al 2016]; see also Lopes et al [2016] and references therein.

Other features

Genotype-Phenotype Correlations

Carvill et al [2014] reviewed more than 50 individuals with STXBP1 encephalopathy with epilepsy and found no correlation between pathogenic variant (including splice, nonsense, and deletion/duplication) or missense variant and phenotype.

Stamberger et al [2016] reviewed 147 individuals with STXBP1 encephalopathy with epilepsy and found no correlation between the type of pathogenic variant (missense or truncating) and cognitive abilities or response to antiepileptic drugs (AEDs).

Penetrance

Almost all individuals with pathogenic variants in STXBP1 had developmental delay, cognitive dysfunction, intellectual disability, and/or epilepsy.

Prevalence

Fewer than 200 individuals with an STXBP1 pathogenic variant have been reported, including isolated STXBP1 encephalopathy with epilepsy and contiguous gene deletion syndromes. Stamberger et al [2016] estimated the prevalence of STXBP1 encephalopathy with epilepsy at 1:91,862 individuals in the Danish population.

Differential Diagnosis

Phenotypic and EEG features associated with STXBP1 pathogenic variants are not sufficient to diagnose STXBP1 encephalopathy with epilepsy. All genes known to be associated with early-infantile epileptic encephalopathy (>30 have been identified; see OMIM Phenotypic Series) should be included in the differential diagnosis of STXBP1 encephalopathy with epilepsy.

Treatable neurometabolic disorders causing early infantile-onset epileptic encephalopathy should be included in the differential diagnosis. These disorders include:

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with STXBP1 encephalopathy with epilepsy, the following evaluations are recommended:

  • Neurologic evaluation
  • Epilepsy consultation (if not done at the time of initial assessment)
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Developmental delay, cognitive dysfunction, and intellectual disability. Physiotherapy, occupational therapy, and speech-language therapy can be beneficial.

Seizure management is symptomatic. The most commonly used AEDs were phenobarbital, valproic acid, and vigabatrin. Clobazam, zonisamide, lamotrigine, and oxcarbamazepine have also been used.

In single cases, a response to vigabatrin, carbamazepine, phenobarbital, or valproic acid and levetiracetam has been reported [Hamdan et al 2009, Deprez et al 2010, Saitsu et al 2010, Mignot et al 2011, Weckhuysen et al 2013, Barcia et al 2014, Romaniello et al 2014, Keogh et al 2015, Romaniello et al 2015, Dilena et al 2016, Yamamoto et al 2016].

In more than 20% of affected individuals, two or more AEDs were used in combination.

About 25% of affected individuals were refractory to AED therapy.

In approximately 20% of affected individuals, seizures were controlled with one or more than one combined anti-seizure medication. In individuals who became seizure-free, AEDs were discontinued between one month and 5.5 years after treatment began [Deprez et al 2010, Romaniello et al 2015, Sampaio et al 2015]. The longest seizure-free period documented following discontinuation of AEDs was approximately 11 years [Deprez et al 2010].

In about 1% of affected individuals, the ketogenic diet was used for seizure management. Response to the ketogenic diet was either slight or none [Saitsu et al 2011, Weckhuysen et al 2013].

Epilepsy surgery was the treatment of choice in two affected individuals: one became seizure-free following corpus callosotomy [Otsuka et al 2010]; the other had a significant reduction in seizure frequency following resection of focal cortical dysplasia [Weckhuysen et al 2013].

Other neurologic findings

  • Severe dystonia, dyskinesia, or choreoathetosis can be treated with monoamine depleters or dopaminergic agents.
  • Hypotonia may lead to feeding difficulties and associated recurrent aspiration pneumonia, which may require G-tube placement.

Behavior disorders can be managed symptomatically with behavioral therapies by psychologists or behavior therapists.

Surveillance

There are no published guidelines for surveillance of individuals diagnosed with STXBP1 encephalopathy with epilepsy. The following assessments and investigations can be performed as needed:

  • Neuropsychological assessment
  • EEG

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

STXBP1 encephalopathy with epilepsy is inherited in an autosomal dominant manner (i.e., a heterozygous STXBP1 pathogenic variant causes the disorder).

Risk to Family Members

Parents of a proband

  • Most probands with STXBP1 encephalopathy with epilepsy reported to date are simplex cases (i.e., a single occurrence in a family) and have the disorder as a result of a de novo pathogenic variant.
  • Rare individuals with STXBP1 encephalopathy with epilepsy have inherited an STXBP1 variant from an asymptomatic parent who has somatic and/or germline mosaicism [Saitsu et al 2011].
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo STXBP1 pathogenic variant. If the STXBP1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the proband most likely has a de novo pathogenic variant. Parental germline mosaicism or parental somatic and germline mosaicism are also possible explanations, especially in families with unaffected parents and more than one affected sib [Saitsu et al 2011].

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband. Individuals with STXBP1 encephalopathy with epilepsy are not known to reproduce.

Other family members. The risk to other family members depends on the status of the proband's parents; however, given that most probands with STXBP1 encephalopathy with epilepsy reported to date have the disorder as a result of a de novo pathogenic variant, risk to family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the STXBP1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for STXBP1 encephalopathy with epilepsy are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 202-387-1968
    Fax: 202-387-2193
    Email: sis@aaidd.org
  • American Epilepsy Society (AES)
  • Canadian Epilepsy Alliance
    Canada
    Phone: 1-866-EPILEPSY (1-866-374-5377)
  • Epilepsy Canada
    Canada
    Phone: 877-734-0873
    Email: epilepsy@epilepsy.ca
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org
  • Medline Plus
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

STXBP1 Encephalopathy with Epilepsy: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
STXBP19q34​.11Syntaxin-binding protein 1STXBP1 databaseSTXBP1STXBP1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for STXBP1 Encephalopathy with Epilepsy (View All in OMIM)

602926SYNTAXIN-BINDING PROTEIN 1; STXBP1
612164EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4; EIEE4

Gene structure. The longest STXBP1 transcript variant, NM_003165.3, has 20 exons [Hamdan et al 2009]. For a detailed summary of gene, transcript, and protein information, see Table A, Gene.

Pathogenic variants. More than 85 pathogenic variants have been reported in affected individuals, identified by sequence analysis (83%), gene-targeted deletion/duplication studies (5%), and chromosomal microarray (12%).

Types of variants detected by sequence analysis (83%) include missense (39%), nonsense (14%), and splice site variants (17%) and small deletion/duplications (13%).

Recurrent pathogenic missense variants are listed in Table 2. Click here (pdf) for a summary of the phenotypes of affected individuals with these variants.

Table 2.

Selected Recurrent STXBP1 Pathogenic Missense Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.364C>T 1p.Arg122TerNM_003165​.3
NP_003156​.1
c.416C>T 2p.Pro139Leu
c.568C>T 3p.Arg190Trp
c.703C>T 4p.Arg235Ter
c.875G>A 5p.Arg292His
c.902+1G>A 6Splice site variant
c.1162C>T 7p.Arg388Ter
c.1217G>A 8p.Arg406His
c.1439C>T 9p.Pro480Leu
c.1651C>T 10p.Arg551Cys

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

Normal gene product. Syntaxin-binding protein 1 (STXBP1 or MUNC18-1), a member of the SEC1 family of membrane-trafficking proteins, is encoded by STXBP1. The transcript variant NM_003165.3 encodes a 603-amino acid protein (NP_003156.1).

STXBP1 is expressed in neurons and plays an important role in synaptic vesicle docking and fusion [Pevsner et al 1994, Swanson et al 1998]. It is necessary for neurotransmitter release in the brain [Verhage et al 2000]. Specifically, STXBP1 modulates the presynaptic vesicular fusion reaction by interacting with vesicle-and target-associated SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins [Shen et al 2007, Gerber et al 2008].

Abnormal gene product. Pathogenic variants of STXBP1 likely impair neurotransmitter release, specifically in GABAergic interneurons, resulting in uncontrolled firing of excitatory neurons [Hussain 2014].

References

Literature Cited

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Chapter Notes

Author Notes

Dr Saadet Mercimek-Mahmutoglu's web page

Dr Mercimek-Mahmutoglu's area of focus: clinical neurometabolic research including epilepsy genetics and treatable neurometabolic disorders

Revision History

  • 1 December 2016 (bp) Review posted live
  • 23 February 2016 (smm) Original submission
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