STXBP1-Related Disorders

Disease Overview

Summary

STXBP1-related disorders include a spectrum of rare neurodevelopmental conditions caused by changes (variants) in the STXBP1 gene.¹

People with STXBP1-related disorders may have a broad range of symptoms including early-onset seizures, developmental delays, intellectual disability, muscular hypotonia, spasticity and ataxia. Affected individuals may also have some features of autism spectrum disorder. People with STXBP1-related disorders may be described as having a developmental and epileptic encephalopathy since most have both developmental delay and epilepsy.¹

Seizures typically develop in the first year of life and may be the first symptom to bring children to medical attention. Epilepsy onset may occur after infancy, generally in early childhood, though onset has been reported in adolescence.^2,3 Children are typically treated with anti-seizure medications (ASMs) to control seizures; however, seizures are not controlled in 25% of patients treated with ASMs. Other treatment options include ketogenic diet, steroids and adrenocorticotropin hormone (ACTH) for infantile spasms and epilepsy surgery including vagal nerve stimulation.¹

The STXBP1 gene encodes a protein that is important for the communication between nerve cells. People with a disease-causing change (pathogenic variant) in the STXBP1 gene do not produce enough of this protein.¹ Inheritance is autosomal dominant.¹

Introduction

STXBP1-related epileptic encephalopathy was initially discovered in 2008 in individuals with a severe, neonatal epilepsy termed Ohtahara syndrome.⁵

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Synonyms

• STXBP1 encephalopathy
• STXBP1 epileptic encephalopathy
• developmental and epileptic encephalopathy 4 [MIM: 612164]

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Signs & Symptoms

Children with STXBP1-related disorders typically present with developmental delay, intellectual disability or cognitive dysfunction and epilepsy. The reported signs and symptoms include:^1,2,3,6

Epilepsy: Up to 90% of affected people develop epilepsy with seizures usually starting within the first year of life (median age of onset is around six weeks) but can begin in the neonatal period or, less commonly, later in childhood or adolescence. Common seizure types include:

• Infantile spasms (about 40% of cases) also known as West syndrome are a type of seizure that occurs in babies and young children typically between 2 and 12 months of age and involve sudden, brief jerking or twitching movements, often accompanied by stiffening of the body.
• Focal seizures are a type of seizure that affects only one side of the brain and body.
• Tonic seizures are sudden, sustained stiffening and rigidity of the muscles.

More than one-third of children stop having seizures at some point during childhood, about 25% have seizures that are difficult to control, even with multiple antiseizure medications (ASMs).

STXBP1-related disorders can occur in the following recognized epilepsy syndromes:¹

• Ohtahara syndrome (OS), also known as early infantile epileptic encephalopathy (EOEE): This rare epilepsy starts very early in life, usually in newborns or young infants. It is characterized by frequent, strong seizures that are hard to treat and by a unique brainwave pattern called burst suppression, seen on EEG tests. Around 1 in 5 people with a variant in the STXBP1 gene have shown signs of Ohtahara syndrome.  It seems to be more frequent in people with both missense variants and protein-truncating variants (PTVs) in the STXBP1 gene.
  • Protein-truncating variants (PTVs) and missense variants are types of gene changes that can change the amino acid sequence of a protein, but they differ in how they impact the protein’s structure and function. PTVs result in the production of a shortened protein while missense variants lead to a single amino acid change within the protein.

• Early myoclonic epileptic encephalopathy: This rare and severe epilepsy starts early in life with jerking movements called myoclonic seizures and shows a burst suppression pattern during sleep on EEG. This syndrome has been seen in very few people with STXBP1-related epilepsy.
• Dravet syndrome: This epilepsy often begins in the first year of life, usually triggered by fevers. The seizures are hard to control and may worsen over time. EEG tests typically show a pattern called spike-wave activity. Only a few people with Dravet syndrome have been found to have variants in the STXBP1
• Lennox-Gastaut syndrome: This epilepsy syndrome is characterized by many types of seizures, especially tonic (stiffening) and myoclonic (jerking) seizures that are very difficult to treat. EEG results show a slow brain pattern with spike-wave bursts that happen less than 2.5 times per second. In one study about 1 out of 115 people with Lennox-Gastaut syndrome had a STXBP1 gene variant.
• Rett syndrome–like symptoms: A few individuals with STXBP1 gene variants have shown signs that look like Rett syndrome, a progressive brain disorder. Children with Rett syndrome usually develop normally at first but then go through a sudden regression, losing language, motor skills and the ability to use their hands. They may also show repetitive hand movements like wringing or clapping, screaming fits or crying that can’t be soothed, signs of autism, breathing issues like breath-holding or rapid breathing, trouble walking or balancing and shaking, seizures, and a smaller-than-normal head size (microcephaly). Only a very few people with Rett-like features have been found to have a variant in the STXBP1

Epilepsy syndromes like EOEE, Dravet syndrome and Lennox-Gastaut syndrome are clinical diagnoses based on seizure types, EEG patterns and developmental features. Variants in the STXBP1 gene are one of several genetic causes of these syndromes. In these cases, the epilepsy syndrome diagnosis is a clinical description of the types of seizures, but the genetic diagnosis of an STXBP1-related disorder is the primary diagnosis that explains why a child has developed epilepsy.⁶

A few people with STXBP1 variants present with a Rett syndrome-like condition, which includes normal development in infancy, followed by regression, loss of purposeful hand use, stereotypic hand movements, ataxia and gait abnormalities and some additional features that may include autistic traits, episodes of hyperventilation or breath-holding and seizures.

Neurologic and developmental problems: All people with STXBP1-related disorders have some degree of developmental delay and/or intellectual disability which can range from mild to profound, including:

• Delayed motor milestones such as head control, rolling, or crawling
  • Less than half of the affected children can walk independently, often several years after typically expected.
• Low muscle tone (hypotonia) in infancy which may progress to or coexist with spasticity (stiff muscle tone)
  • Hypotonia may be an early indication of delayed motor development in children with this disorder and in some children, it may be the first indication of spasticity (stiffy muscles).
• Gait abnormalities including coordination problems (ataxia)
• Movement disorders such as twisting, abnormal postures and repetitive movements (dystonia), tremors and dyskinesia (involuntary, erratic movements)
• Limited expressive language development where over 90% of children have few or no spoken words but receptive language (understanding language) may be relatively better preserved, and children develop other communication skills

• Neurobehavioral problems that may include autism spectrum disorder (reported in 16–31% of affected people), sleep disturbances and social communication deficits

These signs may change in terms of severity at any point during infancy or childhood. However, new-onset neurological symptoms after the first three years of life are not common.

Other signs and symptoms may include:¹

• Damage to the parts of the brain that process vision (cortical visual impairment) in some children
• Gastrointestinal issues in about 47% including constipation, reflux and feeding difficulties; 13% require a G-tube
• Small head (microcephaly), abnormal curved spine (scoliosis), joint laxity and crossed eyes (strabismus) occur occasionally
• EEG findings commonly show burst suppression, hypsarrhythmia (a specific pattern of electrical activity in the brain, a chaotic and disorganized pattern of high-voltage, slow waves with multifocal spikes) and focal/multifocal discharges

• Abnormalities of the brain include cerebral atrophy, delayed myelination and corpus callosum thinning (in around 24%)

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Causes

STXBP1-related disorders are caused by changes (pathogenic variants) in the STXBP1 gene.

The STXBP1 gene encodes the STXBP1 protein, also known as Munc-18, which is crucial for synaptic vesicle release, a fundamental process for neuron-to-neuron communication. This protein is a core component of the SNARE complex, the molecular machinery that drives vesicle fusion, allowing neurotransmitters to be released into the synaptic cleft and enabling signal transmission across neurons.^7,8 Pathogenic STXBP1 variants result in loss of function (haploinsufficiency) where not enough STXBP1 protein is produced. There is also emerging evidence that certain STXBP1 variants may also create some aggregation of the altered STXBP1 protein, which may suggest additional disease mechanisms that are not fully understood yet.¹

Disease-causing variants in the STXBP1 gene may be due to missense, nonsense, frameshift and splice-site variants as well as whole gene deletions.³ Missense variants occur where a single base pair change results in a different amino acid being incorporated into the protein, which can alter the protein’s function, sometimes causing a disease. Nonsense variants lead to the premature termination of protein synthesis, resulting in a shortened, often non-functional, protein. A frameshift variant is a variant that alters the reading frame of a DNA sequence, leading to a misaligned sequence of codons and a different amino acid sequence being produced. Splice-site variants occur in a process where different combinations of exons (coding regions) are included in the final RNA product, resulting in different proteins.

STXBP1-related disorders follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.¹

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Affected populations

STXBP1-related disorders are rare and affect individuals of all ethnic backgrounds with equal prevalence in males and females. The estimated incidence is between 1 in 26,000 and 1 in 30,000 live births or approximately 3.3–3.8 per 100,000.^1,4

As of 2022, about 534 people with STXBP1-related disorders have been described in the medical literature and there are an estimated 750 cases known worldwide.⁴

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Disorders with Similar Symptoms

Doctors often use different frameworks when describing an individual’s symptoms and may use distinct terminology to refer to the presentation of epilepsy and the underlying cause. For example, a child may be diagnosed with West syndrome due to a variant in STXBP1 (underlying genetic cause).

As commented before, several epilepsy syndromes such as Ohtahara syndrome, West syndrome, Dravet syndrome and Lennox-Gastaut syndrome, have been associated with STXBP1-related disorders. These epilepsy syndromes share overlapping features, and it is possible for an individual with STXBP1-related disorder to receive one or more of the following diagnoses over the course of their childhood. In addition, several of these conditions have more than one genetic cause, meaning that they are not only caused by STXBP1 gene variants, but by variants in other genes as well.

The following conditions share some symptoms with STXBP1-related disorders:¹

• Vitamin B6-dependent epilepsies: Theses conditions are characterized by seizures that only improve until the child is given vitamin B6 (or related forms like pyridoxal phosphate). It is caused by variants in genes ALDH7A1, PNPO, or PLPBP. Early treatment with the right kind of B6 can prevent long-term problems.
• Biotinidase deficiency: This condition is caused by a lack of enzyme needed to recycle biotin, a B-vitamin. It is characterized by seizures, skin rashes and hearing or vision problems and is easily treated with biotin supplements.
• Glucose transporter type 1 deficiency (Glut1 DS): In this condition, the brain can’t get enough glucose (sugar) which it needs to function. Symptoms include seizures, movement problems and developmental delays. It is treated with a ketogenic diet (high-fat, low-carb) which provides an alternative fuel source for the brain.
• Creatine deficiency disorders: These conditions affect the brain’s energy supply. They are characterized by seizures, intellectual disability and speech delays. Some forms are treated with creatine supplements; others may need more targeted treatment.
• Holocarboxylase synthetase deficiency: This is a rare condition that affects how the body uses biotin. It is characterized by seizures, breathing problems and skin issues. Biotin treatment can be lifesaving if started early.
• Serine deficiency disorders: Serine is a building block for brain development. Lack of it can cause seizures, microcephaly (small head size) and delays. Some types can be treated with serine supplements.

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Diagnosis

STXBP1-related disorder may be suspected in any child with an unexplained early infantile epileptic encephalopathy or new-onset infantile spasms. The diagnosis of a STXBP1-related disorder is currently made by looking at the DNA sequence of the STXBP1 gene via targeted genetic panels or whole exome sequencing, a genetic test that analyzes the coding regions (exons) of all genes in a person’s genome. The STXBP1 gene is included on most epilepsy, neurodevelopmental and autism/intellectual disability gene panels. In rare cases, a microdeletion (loss) containing the STXBP1 gene may be found on a chromosomal microarray, a genetic test that examines an individual’s DNA to identify small, missing, or extra sections of chromosomes.

Clinical Testing and Work-Up
In addition to confirming the diagnosis with genetic testing, electroencephalograms (EEGs) and magnetic resonance imaging (MRI) of the brain are usually done as part of the initial evaluation.

• EEGs may show diffuse background slowing with multifocal and/or generalized interictal discharges, hypsarrhythmia, or seizures.
• MRI of the brain may be indicated to rule out an underlying structural brain abnormality. As the initial MRI brain does not typically show any abnormality in these children, it is not formally indicated to perform this exam. However, neurologists may request a brain MRI in children with seizures, developmental delays or atypical findings on a neurologic exam.

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Standard Therapies

Treatment

Currently, there is no cure or specific treatment for STXBP1-related disorders.  Treatment is focused on managing symptoms and improving the person’s quality of life. Because each child is affected differently the care plan is often tailored to each individual. Patients need to be cared for by a team of many types of medical and therapy professionals who should work together in a coordinated way.

• Pediatric neurologists will generally be involved to aid in the management of seizures/epilepsy and movement disorders.
• Evaluations by physical, occupational, and speech therapists will identify needs for ongoing therapies and help establish the child’s qualification for early intervention services.
• Physiatrists (pediatric rehabilitation specialists) may be helpful to identify therapy and equipment needs and help optimize function.
• Dieticians may be helpful for ensuring adequate growth; a dietician specializing in ketogenic diet (KD) would be a necessary part of the treatment team if KD was initiated for seizure management.
• Neuropsychiatric testing may be indicated during childhood to assess cognitive impairments and intellectual disability.

After diagnosis, several evaluations may be recommended, including:

• A developmental evaluation, which looks at motor skills, thinking, learning and communication abilities and helps to determine if a child qualifies for early intervention or special education
• A neurological exam, possibly including a brain MRI and EEG (a test that measures brain activity) if seizures are suspected
• An assessment of movement disorders to see if there are issues like tremors, stiffness, or uncontrolled movements
• A feeding and nutrition evaluation, including screening for problems like choking, difficulty swallowing (dysphagia), or poor weight gain
• Neuropsychiatric screening, especially for children over 12 months, to look for signs of behavioral or emotional challenges

Genetic counseling is recommended for the family to help them understand the genetics of the condition and what it means for other family members.

Seizure control is often one of the most difficult parts of managing STXBP1-related disorders. There is no single medication that works for everyone. Some children do well on one anti-seizure medication (ASM) while others may need two or more drugs to get their seizures under control. For infantile spasms, treatments like ACTH, high-dose steroids, or vigabatrin may be used.

Some affected people improve with a high-fat, low-carbohydrate diet (ketogenic diet) but require strict food control and careful medical supervision.

Devices like vagus nerve stimulators (VNS) which send electrical signals to the brain and help control seizures, have been used in some children with this condition.

Based on the specific symptoms, other treatments may include:

• Movement issues can be managed with physical and occupational therapy and are essential to help with mobility and avoid joint stiffness or injury.
• Feeding problems may require thickened liquids, feeding therapy, or feeding tubes (such as a G-tube), a surgically placed feeding tube that delivers nutrition, fluids and medications directly into the stomach if swallowing is unsafe.
• Constipation can be managed with stool softeners or other medications.
• Communication difficulties, which may benefit from augmentative and alternative communication (AAC) methods can be used to augment or replace spoken language for people who have difficulty producing or understanding speech. These can include methods such as picture boards or speech-generating devices.

From a young age, early intervention services can provide in-home therapy to address speech, movement and sensory challenges. In the U.S., these services are available from birth to age 3 through federally funded programs. From age 3 to 5, children can access developmental preschool programs through their school district. An Individualized Education Plan (IEP) can be created to tailor the learning environment to the child’s needs, and this plan is reviewed every year.

As children get older, support continues through school and may include transition planning for adulthood. For children who do not qualify for an IEP, a 504 plan can offer classroom support like extra time, special seating, or help with technology.

Families may also qualify for state support services such as enrollment in the Developmental Disabilities Administration (DDA) or receiving Supplemental Security Income (SSI) for children with disabilities.

Some children benefit from therapies used for autism, such as applied behavior analysis (ABA) which teaches skills and manages behaviors through structured sessions. Behavioral challenges like aggression, attention-deficit/hyperactivity disorder (ADHD) or anxiety may require help from a developmental pediatrician or child psychiatrist. Medication may be used when necessary.

Although there are no formal surveillance guidelines for STXBP1-related disorders, regular follow-ups help identify changing needs.

Important aspects of management include psychosocial support for the family, development of an appropriate education plan and assessment of available community resources.

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Clinical Trials and Studies

The following institutions have specialists in STXBP1-related disorders:

Children’s Hospital of Philadelphia – Epilepsy Neurogenetics Initiative (ENGIN)
3401 Civic Center Blvd.
Philadelphia, PA 19104
Phone: 267-425-0515
Website: https://www.chop.edu/centers-programs/epilepsy-neurogenetics-initiative-engin

Children’s Hospital Colorado
Anschutz Medical Campus
13123 East 16th Avenue
Aurora, CO 80045
Phone: 720-777-1234
Website: https://www.childrenscolorado.org/doctors-and-departments/departments/neuroscience-institute/programs/neurology/

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

1. Mercimek-Andrews S. STXBP1 Encephalopathy with Epilepsy. 2016 Dec 1 [Updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK396561/ Accessed May 29, 2025.
2. Abramov D, Guiberson NGL, Burré J. STXBP1 encephalopathies: Clinical spectrum, disease mechanisms, and therapeutic strategies. Journal of Neurochemistry. 2020. doi:10.1111/jnc.15120.
3. Stamberger H, Nikanorova M, Willemsen MH, et al. STXBP1encephalopathy. Neurology. 2016;86(10):954-962. doi:10.1212/wnl.0000000000002457.
4. López-Rivera JA, Pérez-Palma E, Symonds J, et al. A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants. Brain. 2020;143(4):1099-1105. doi:10.1093/brain/awaa051.
5. Saitsu H, Kato M, Mizuguchi T, et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nature Genetics. 2008;40(6):782-788. doi:10.1038/ng.150.
6. Xian J, Parthasarathy S, Ruggiero SM, et al. Assessing the landscape of STXBP1-related disorders in 534 individuals. Brain. 2022;145(5):1668-1683. doi:10.1093/brain/awab327
7. STXBP1-Related Disorders. Children’s Hospital of Philadelphia. https://www.chop.edu/conditions-diseases/stxbp1-related-disorders Accessed May 29, 2025.
8. Deák, F, Xu Y, Chang, W, et al. Munc18-1 binding to the neuronal SNARE complex controls synaptic vesicle priming. The Journal of Cell Biology. 2009;184(5), 751–764. doi:10.1083/jcb.200812026.
9. Guiberson NGL, Pineda A, Abramov D, et al. Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones. Nature Communications. 2018;9(1). doi:10.1038/s41467-018-06507-4.

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