Clinical characteristics.

STXBP1 encephalopathy with epilepsy is characterized by early-onset developmental delay, intellectual disability or cognitive dysfunction, and epilepsy. 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, atonic, absence, and focal seizures. EEG abnormalities can include focal epileptic activity, burst suppression, hypsarrhythmia, or generalized spike-and-slow waves. Other neurologic findings include abnormal tone, movement disorders (especially ataxia and dystonia), and behavioral issues and autism spectrum disorder. Feeding difficulties are common.

Diagnosis/testing.

The diagnosis is established in a proband with a heterozygous STXBP1 pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: Standard treatments for developmental, cognitive, and neurobehavioral issues. The most commonly used anti-seizure medications (ASMs) are phenobarbital, valproic acid, and vigabatrin. About 20% of individuals require more than one ASM and approximately 25% are refractory to ASM therapy. Severe dystonia, dyskinesia, and choreoathetosis can be treated with monoamine-depleting or dopaminergic agents. Treatment per orthopedics, physical medicine and rehabilitation, physical therapy, and occupational therapy to help avoid contractures and falls, with positioning and mobility devices as needed. Feeding difficulties and constipation are managed per standard protocols. Social work support and care coordination as needed.

Surveillance: Monitor developmental progress and educational needs, seizures, changes in tone, movement disorders, behavioral issues, growth and nutritional status, evidence of constipation, and family needs at each visit; follow-up EEG as needed; occupational and physical therapy assessments as needed.

Genetic counseling.

STXBP1 encephalopathy with epilepsy is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Most individuals reported to date represent simplex cases (i.e., the only family member known to be affected) and have the disorder as the 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 and preimplantation genetic testing are available.

Suggestive Findings

STXBP1 encephalopathy with epilepsy should be considered in individuals with early-onset refractory seizures, developmental delay, and intellectual disability or cognitive dysfunction, particularly those with the following epilepsy features and seizure types.

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

Other features

• Mild-to-profound intellectual disability
• Tone abnormalities: spasticity, hypotonia
• Movement disorders including ataxia, dystonia, dyskinesia, tremor, or choreoathetosis
• Behavioral issues
• Autism spectrum disorder

Establishing the Diagnosis

The diagnosis of STXBP1 encephalopathy with epilepsy is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in STXBP1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of a heterozygous STXBP1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of STXBP1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Clinical Description

STXBP1 encephalopathy with epilepsy is characterized by developmental delay, intellectual disability or cognitive dysfunction, and epilepsy. To date, about 500 affected individuals have been reported [Vatta et al 2012, Allen et al 2013, Tucker et al 2014, Di Meglio et al 2015, Ehret et al 2015, Kwong et al 2015, Allen et al 2016, Dilena et al 2016, Guacci et al 2016, Helbig 2016, Lopes et al 2016, Marchese et al 2016, Nambot et al 2016, Yamamoto et al 2016, Xian et al 2022].

Developmental delay. Generalized hypotonia or absence of head control was reported in fewer than 50% of affected individuals. Developmental trajectories of 48 individuals with STXBP1 encephalopathy with epilepsy showed evidence of early developmental delays in gross motor, fine motor, and speech in most individuals [Balagura et al 2022]. Later seizure onset correlated in general with better developmental outcomes, whereas there was no significant correlation between neurodevelopmental outcomes and age at seizure remission.

In a natural history study of adults with STXBP1 encephalopathy with epilepsy, 71% of adults were nonverbal. Only 50% of adults were walking independently, and 39% were wheelchair bound. The first signs of developmental delay were present in the first year of life in 76% of adults. All adults were dependent on caregivers for most of their activities of daily living [Stamberger et al 2022].

Episodic developmental regression was reported in 59% of adults with STXBP1 encephalopathy with epilepsy but did not always correlate with increased seizure frequency.

Intellectual disability / cognitive dysfunction is present in all individuals with STXBP1 encephalopathy with epilepsy. In 48 individuals with STXBP1 encephalopathy with epilepsy, intellectual disability ranged from severe to profound in 87% of individuals, and mild intellectual disability was reported in 13% [Balagura et al 2022]. In a separate study, intellectual disability was reported in 90% of individuals older than age 11 years; 64% of individuals had severe or profound intellectual disability and 2% had mild intellectual disability. Additionally, about 38% of individuals were nonverbal [Xian et al 2022]. In the natural history study of adults with STXBP1 encephalopathy with epilepsy, 87% of adults had severe or profound intellectual disability [Stamberger et al 2022].

Seizures. Age of seizure onset ranges from six hours of life to age 13 years [Milh et al 2011, Di Meglio et al 2015]. In two large studies of individuals with STXBP1 encephalopathy with epilepsy, seizure onset was within the first year of life in 84.7%-89% of individuals [Xian et al 2022, Xian et al 2023].

Focal-onset seizures, generalized-onset seizures, and infantile spasms were the most common seizure types [Xian et al 2022]. Focal-onset seizures were reported in 66.6% of individuals and infantile spasms in 40.3%-50% [Xian et al 2022, Xian et al 2023]. In a small number of individuals, simple febrile seizures, myoclonic atonic seizures, typical absence seizures, and hemiclonic seizures were reported [Xian et al 2022]. More than 60% of affected individuals had more than one seizure type during their lifetime.

Epilepsy course was reported for 48 individuals with STXBP1 encephalopathy with epilepsy. The number of anti-seizure medications (ASMs) used to treat each individual ranged from one to eight different ASMs and included phenobarbital (50%), valproic acid (42%), vigabatrin (31%), ACTH (27%), pyridoxine (31%), levetiracetam (31%), benzodiazepines (23%), topiramate (23%), and carbamazepine (23%). In more than 20% of individuals, two or more ASMs were used in combination. About 25% of affected individuals were refractory to ASM therapy [Balagura et al 2022]. In individuals who became seizure-free, ASMs 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 after discontinuation of ASMs 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 ranged from a mild reduction in seizure frequency to no response in early studies [Saitsu et al 2011, Weckhuysen et al 2013]. In a recent study, effects of the ketogenic diet were reported in 12 individuals with STXBP1 encephalopathy with epilepsy. Complete or near complete seizure freedom was reported in 33% of those individuals [Nam et al 2022].

Epilepsy surgery was the treatment of choice in two affected individuals: one became seizure-free following corpuscallosotomy [Otsuka et al 2010]; and the other had a significant reduction in seizure frequency following resection of focal cortical dysplasia [Weckhuysen et al 2013]. In another study, epilepsy surgery was performed in one individual with significant improvements in seizures [Balagura et al 2022].

In 30 adults with STXBP1 encephalopathy with epilepsy, 80% had refractory seizures and 37% had long periods without seizures [Stamberger et al 2022].

Epilepsy or electroclinical syndromes. Historically, several electroclinical syndromes have been reported in association with pathogenic variants in STXBP1. In a large study of 534 individuals with STXBP1 encephalopathy with epilepsy, 26% of individuals had specific electroclinical syndromes, including infantile spasms syndrome (previously termed West syndrome, 15%), Ohtahara syndrome (9%), and Rett syndrome phenotype (2%) [Xian et al 2022].

• Ohtahara syndrome is characterized by frequent generalized tonic refractory seizures and burst suppression patterns on EEG. Age of seizure onset is typically during the neonatal or early infantile period. Approximately 20% of individuals with a STXBP1 pathogenic variant were reported to have features consistent with Ohtahara syndrome [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].
• Infantile spasms syndrome 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]. Thirteen individuals with a STXBP1 pathogenic variant were reported with a 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 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-Gastaut 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-Gastaut syndrome was identified with STXBP1 encephalopathy with epilepsy [Allen et al 2013].
• Rett syndrome phenotype. Three individuals with Rett syndrome phenotype have been identified with an STXBP1 pathogenic variant [Olson et al 2015, Romaniello et al 2015, Lopes et al 2016]. Rett syndrome, a progressive neurodevelopmental disorder, is characterized by apparently normal motor and cognitive development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive and stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly.

Electroencephalography (EEG) abnormalities have been 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, Yamamoto et al 2016].

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

Movement disorders. Reported movement disorders in individuals with STXBP1 encephalopathy with epilepsy include hypomimia, bradykinesia, tremor, ataxia, dyskinesia, dystonia, or choreoathetosis. In 30 adults, movement disorders were present in 87%. The most common types were hypomimia (83%), bradykinesia (63%), and tremor (56%) [Stamberger et al 2022]. Tremor and ataxia were present in about 40% of individuals older than age 11 years [Xian et al 2022].

Neurobehavioral disorders include autism spectrum disorder, autistic-like features, hyperactivity, and self-aggressive behaviors. In a natural history study of adults with STXBP1 encephalopathy with epilepsy, significant behavioral issues were reported in 65% of adults, including aggressive behavior, hyperactivity, self-mutilation, compulsive symptoms, and (rarely) psychotic episodes. Autism spectrum disorder or autistic features were present in 42% of adults [Stamberger et al 2022]. Significant sleep problems have included either problems with initiation or maintenance of sleep in 20% of individuals [Stamberger et al 2022].

Gastrointestinal manifestations. In 47% of individuals gastrointestinal manifestations were reported, including constipation, poor weight gain, and gastroesophageal reflux disease. Gastrostomy tube feeding was needed in 13% of individuals [Stamberger et al 2022].

Microcephaly was reported in fewer than ten individuals [Kwong et al 2015, Allen et al 2016, Stamberger et al 2016, Yamamoto et al 2016].

Other

• Scoliosis (4 individuals) [Stamberger et al 2022]
• Joint laxity (3 individuals) [Stamberger et al 2022]
• Strabismus (2 individuals) [Boutry-Kryza et al 2015, Dilena et al 2016]

Brain MRI findings were 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. Brain MRI findings in 29 individuals with STXBP1 encephalopathy with epilepsy showed 76% had normal brain MRIs. Cerebral atrophy was present in 14% of individuals. Nonspecific brain MRI features were found such as right parietal gyral asymmetry and FLAIR hyperintensities (n=1), a small infarction (n=1), small hippocampi with incomplete rotation (n=1), and suspected temporal myelination defect (n=1). One adult had a normal brain MRI at age four years and age 13 years, but mild cerebral atrophy was identified in adulthood [Stamberger et al 2022].

Genotype-Phenotype Correlations

In more than 50 individuals with STXBP1 encephalopathy with epilepsy, no correlation was found between phenotype and the type of pathogenic variant (including splice, nonsense, deletion/duplication, or missense variant) [Carvill et al 2014]. In 147 individuals, no correlation between the severity of cognitive dysfunction or response to ASM and the type of pathogenic variant (missense or truncating) was identified [Stamberger et al 2016].

In a study of recurrent pathogenic variants (p.Arg406His/Cys, p.Arg292Cys/His/Leu, p.Arg551Cys/Gly/His/Leu, p.Pro139Leu, p.Arg190Trp) identified in more than ten individuals with STXBP1 encephalopathy with epilepsy, there were no identifiable genotype-phenotype correlations for these variants. Individuals with protein-truncating variants and deletions in STXBP1 showed significant phenotypic similarities. Individuals with protein-truncating variants and deletions had West syndrome (odds ratio [OR] = 1.6, 95% confidence interval [CI] = 0.95-2.73) and infantile spasms and ataxia (OR = 1.59, 95% CI = 1.08-2.35). Individuals with missense variants had a developmental epileptic encephalopathy phenotype (OR = 2.05, 95% CI = 1.28-3.32). However, there were no phenotypic similarities between individuals with the recurrent variants in STXBP1 [Xian et al 2022].

Penetrance

STXBP1 encephalopathy with epilepsy is expected to be completely penetrant.

Prevalence

More than 500 individuals with an STXBP1 encephalopathy with epilepsy have been reported in a recent study [Xian et al 2022]. Stamberger et al [2016] estimated the prevalence of STXBP1 encephalopathy with epilepsy to be 1:91,862 individuals in the Danish population.

Costain et al [2019] reported that STXBP1 encephalopathy with epilepsy was one of the most common causes of developmental epileptic encephalopathy.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with STXBP1 encephalopathy with epilepsy, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for STXBP1 encephalopathy with epilepsy. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

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 [Stamberger et al 2022].

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 an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most individuals reported to date with STXBP1 encephalopathy with epilepsy represent simplex cases (i.e., the only family member known to be affected) and have the disorder as the result of a de novo STXBP1 pathogenic variant.
• Rarely, a proband with STXBP1 encephalopathy with epilepsy has the disorder as the result of an STXBP1 pathogenic variant inherited from an asymptomatic parent with germline (or somatic and germline) mosaicism [Saitsu et al 2011, Møller et al 2019, Stamberger et al 2022].
  • Parental somatic and germline mosaicism was reported in the asymptomatic father of a child diagnosed with Ohtahara syndrome [Saitsu et al 2011].
  • Presumed parental germline mosaicism was reported in a family in which the STXBP1 pathogenic variant identified in two affected sibs was not identified in parental leukocyte DNA [Stamberger et al 2022].
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Saitsu et al 2011, Møller et al 2019, Stamberger et al 2022]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

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 pathogenic variant is 50%.
• If the STXBP1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental mosaicism [Saitsu et al 2011, Møller et al 2019, Stamberger et al 2022].
• If the parents have not been tested for the STXBP1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low but still increased for STXBP1 encephalopathy with epilepsy because of the possibility of parental mosaicism.

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

Other family members. Given that most probands with STXBP1 encephalopathy with epilepsy reported to date have the disorder as a result of a de novo pathogenic variant, the risk to other 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/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

STXBP1 encodes syntaxin-binding protein 1 (STXBP1 or MUNC18-1), a member of the SEC1 family of membrane-trafficking proteins. 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].

Mechanism of disease causation. Loss of function. Pathogenic variants of STXBP1 likely impair neurotransmitter release, specifically in GABAergic interneurons, resulting in uncontrolled firing of excitatory neurons [Hussain 2014].

Author Notes

Dr Saadet Mercimek-Andrews's areas of focus are neurometabolic disorders, epilepsy genetics, and neurogenetics. See:

• www.ualberta.ca/medical-genetics/people/faculty/saadet-andrews.html
• www.wchri.org/members-and-trainees/find-a-researcher/saadet-andrews

Author History

Saadet Mercimek-Andrews, MD, PhD, FCCMG, FRCPC (2016-present)

Yannay Khaikin, BSc; The Hospital for Sick Children (2016-2023)

Revision History

• 28 September 2023 (sw) Comprehensive update posted live
• 1 December 2016 (bp) Review posted live
• 23 February 2016 (smm) Original submission

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