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.

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).

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

• Ohtahara syndrome (OMIM 308350) is characterized by frequent generalized tonic refractory seizures and burst suppression patterns on EEG. Age of onset is neonatal or early infantile. Approximately 20% of individuals with a STXBP1 pathogenic variant were reported to have the clinical phenotype of Ohtahara syndrome, either as single case reports or small cohorts of epileptic encephalopathy [Otsuka et al 2010, Saitsu et al 2012, Kodera et al 2013, Weckhuysen et al 2013, Tso et al 2014, Di Meglio et al 2015, Allen et al 2016, Stamberger et al 2016].
• West syndrome (OMIM 308350) is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG.
  Five of 192 individuals with infantile spasms had STXBP1 encephalopathy with epilepsy [Otsuka et al 2010, Allen et al 2013].
  13 individuals with a STXBP1 pathogenic variant were reported with clinical phenotype of infantile spasms, either as single case reports or small cohorts of epileptic encephalopathy [Saitsu et al 2008, Deprez et al 2010, Saitsu et al 2010, Weckhuysen et al 2013, Di Meglio et al 2015, Romaniello et al 2015, Lopes et al 2016].
• Early myoclonic epileptic encephalopathy, characterized by myoclonic seizures and burst suppression pattern in sleep on EEG, was identified in two individuals with STXBP1 encephalopathy with epilepsy [Saitsu et al 2012, Kodera et al 2013].
• Dravet syndrome (OMIM 607208) is characterized by fever-induced refractory seizures with age of onset usually within the first year of life. EEG patterns typically show generalized spike-wave activity as seizures progress. Three of 80 individuals with Dravet syndrome were identified with STXBP1 encephalopathy with epilepsy [Carvill et al 2014].
• Lennox-Gaustaut syndrome is characterized by multiple seizure types particularly tonic and myoclonic refractory epilepsy. EEG shows slow background and spike-wave bursts at frequencies less than 2.5 per second. One of 115 individuals with Lennox-Gaustaut syndrome was identified with STXBP1 encephalopathy with epilepsy [Allen et al 2013].
• Rett syndrome phenotype. Three individuals with the Rett syndrome phenotype have been identified with STXBP1 encephalopathy with epilepsy [Olson et al 2015, Romaniello et al 2015, Lopes et al 2016].

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

• Microcephaly was found in fewer than ten individuals [Kwong et al 2015, Allen et al 2016, Stamberger et al 2016]; see also Yamamoto et al [2016] and references therein.
• Failure to thrive was reported in a small number of affected individuals [Milh et al 2011, Weckhuysen et al 2013, Kwong et al 2015, Nambot et al 2016].
• Strabismus was reported in two affected individuals [Boutry-Kryza et al 2015, Dilena et al 2016].
• Findings other than mild dysmorphic facial features in individuals with a contiguous gene deletion:
  • Absent thumbnails and hypoplastic second fingernails (1 individual) [Mignot et al 2011]
  • Cleft lip and palate, ventricular septal defect, overlapping fingers, small penis (1 individual) [Saitsu et al 2012]
  • Short and broad fingers and broad feet [Campbell et al 2012]
  • Dysplastic right kidney, ureterocele, umbilical hernia (1 individual) [Matsumoto et al 2014]
  • Cleft lip/palate, umbilical hernia, mild dysmorphic facial features, dilated renal pelvis, microcephaly (1 individual) [Nicita et al 2015]

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.

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.

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:

• If a parent of the proband has the STXBP1 pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the STXBP1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (~1%) because of the possibility of either parental germline mosaicism or somatic mosaicism that includes the germline [Saitsu et al 2011].

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.

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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