NORD gratefully acknowledges Dylan Brock, MD, Children’s Hospital Colorado, Charlene Son Rigby, MBA, STXBP1 Foundation, and Ingo Helbig, MD Children’s Hospital of Philadelphia, for the preparation of this report.
STXBP1-related disorders comprise a spectrum of rare autosomal dominant neurodevelopmental conditions caused by changes in the STXBP1 gene. STXBP1-related epileptic encephalopathy was initially discovered in 2008 in individuals with a severe, neonatal epilepsy termed Ohtahara syndrome (Saitsu et al, 2008). In the years following, the spectrum of patient presentations expanded significantly. Individuals with STXBP1-related disorders experience a broad range of symptoms including early-onset seizures, developmental delays, intellectual disability, muscular hypotonia, spasticity and ataxia. Affected individuals may also exhibit some features of autism spectrum disorder. Individuals with STXBP1-related disorders may be also described as having a developmental and epileptic encephalopathy since most experience both developmental delay and epilepsy.
The STXBP1 gene encodes the syntaxin-binding protein 1, which is integral to communication between nerve cells, facilitating the release of neurotransmitter into the synapse. Individuals with a pathogenic variant in the STXBP1 gene do not produce enough syntaxin-binding protein 1. The estimated incidence rate for STXBP1-related disorders is approximately 1 in 30,000 (Lopez-Rivera et al, 2020).
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 (Stamberger et al, 2016, Ambramov et al, 2020). Individuals 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.
Children with STXBP1-related disorders typically present with seizures and/or delays in meeting early developmental milestones. Epilepsy is diagnosed in up to 85% of individuals with STXBP1-related disorders, often developing very early in life; the median age of seizure onset is as early as six weeks, though onset may range from the immediate postnatal period to adolescence (Abramov et al, 2020, Stamberger et al, 2016). A broad spectrum of seizure types has been reported, including infantile or epileptic spasms, focal-onset seizures, and tonic seizures; up to 40% of children with STXBPI-related disorders develop infantile spasms. Epilepsy in children with STXBP1-related disorders is unpredictable and may prove difficult to treat, especially early in the course, often requiring concurrent use of multiple ASMs. More than a third of children with STXBP1-related disorders achieve seizure freedom during childhood.
In some children, delays in achieving early developmental milestones may be the first sign of a STXBP1-related disorder. This may manifest as a failure to achieve head control, roll over or crawl within the expected timeframe. Low muscle tone (hypotonia) may be an early indication of delayed motor development in children with this disorder; in a subset of children, hypotonia may be the first indication of spasticity. All children with a STXBP1-related disorder have some degree of neurodevelopmental delays and/or intellectual disability (Stamberger et al, 2016). Independent walking is achieved in less than half of children with STXBP1-related disorders, often several years after typically expected. The development of expressive language skills (e.g., ability to speak more than 2-3 words) is observed in only a small minority of children diagnosed with STXBP1-related disorders (more than 90% of children will not acquire expressive language); however, children may have relatively spared receptive language and develop other means of communication. Features of autism spectrum disorder have been reported as well (reports ranging from 16-31%; Stamberger et al, 2016).
A variety of movement disorders and muscle tone abnormalities are also associated with STXBP1-related disorders, including hypotonia; spasticity (i.e., stiff muscle tone); dystonia (i.e., repetitive muscle contractures causing twisting movements); ataxia (e.g., motor incoordination, unsteady gait); tremor and dyskinesias (involuntary, erratic movements). These signs may emerge or evolve in terms of severity at any point during infancy or childhood. However, new-onset neurological symptoms beyond the first three years of life are not common. Cortical visual impairment is seen in some children with STXBP1-related disorders.
STXBP1-related disorders are caused by changes, or pathogenic variants in the STXBP1 gene, which is located on chromosome 9. These are autosomal dominant disorders, meaning that the symptoms manifest when one of two copies (alleles) of the STXBP1 gene are affected by a pathogenic change. These pathogenic variants are typically de novo, meaning that they are unique to the child, and not inherited from either parent. The risk of disease is the same for males and females. Disease-causing variants in the STXBP1 gene may be due to missense, nonsense, frameshift, and splice-site alterations as well as whole gene deletions; identified pathogenic variants are distributed throughout the gene (Abramov et al, 2020).
The STXBP1 protein, also known as Munc-18, plays a role in synaptic vesicle release, a key aspect of communication between neurons. The STXBP1 protein is part of the SNARE complex, which mediates vesicle fusion to release neurotransmitter into the synapse (Deak et al, 2009). Pathogenic STXBP1 variants result in haploinsufficiency, where not enough STXBP1 protein is produced. There is also emerging evidence that certain types of STXBP1 mutations may also create some aggregation of the mutant STXBP1 protein, which may hint at additional disease mechanisms that are not fully understood yet.
STXBP1-related disorders are rare, affecting males and females equally. Approximately 282 individuals have been described in the literature, and there are an estimated 750 cases known worldwide. Estimated incidence rate is between 3.3 – 3.8 per 100,000 births (Lopez-Rivera et al, 2020). Individuals with STXBP1-related disorders are from families with various ethnic backgrounds in North America, South America, Europe, Africa and Asia.
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. The STXBP1 gene is included on most epilepsy, neurodevelopmental, and autism/intellectual disability gene panels. In rare cases, a microdeletion containing the STXBP1 gene may be found on a chromosomal microarray.
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 generally obtained as part of the initial evaluation.
Currently, there are no curative, disease-altering, or specific therapies available for individuals with STXBP1 encephalopathy. Medical management is principally symptomatic and supportive. Given the wide spectrum of symptoms and severity, the specific treatment plan is often highly individualized. In general, a multidisciplinary team approach may be the most effective way to optimize and the individual’s function. Pediatric subspecialists commonly involved in the care of children with STXBP1 encephalopathy include neurologists, physiatrists, dieticians, gastroenterologists, ophthalmologists, physical and occupational therapists and speech pathologists.
During certain aspects of the disease course, seizure control may be challenging and may be a difficult health issue to manage. No single anti-seizure medication has been found to be uniformly effective for children with STXBP1 encephalopathy. While some individuals respond well to treatment with a single medication, multiple anti-seizure medications are necessary in other individuals for adequate seizure control. For infantile spasms, a common seizure type among children with this diagnosis, the first line therapies include ACTH, high dose prednisone or vigabatrin. Dietary modifications such as the ketogenic diet (KD) have shown variable improvement in some individuals. Importantly, KD as an adjunctive therapy for seizure control necessitates rigid, often burdensome, dietary changes and must only be implemented under close medical supervision. Vagal nerve stimulation (VNS) has also been used in some patients with STXBP1-related disorders.
An emphasis should be placed on early intervention therapies such as physical therapy, occupational therapy and speech and augmentative communication therapy. Important aspects of management include psychosocial support for the family, development of an appropriate education plan and assessment of available community resources.
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
Children’s Hospital Colorado
Anschutz Medical Campus
13123 East 16th Avenue
Aurora, CO 80045
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Abramov D, Guiberson NGL, Burré J. STXBP1 encephalopathies: Clinical spectrum, disease mechanisms, and therapeutic strategies. Journal of Neurochemistry. 2020. doi:10.1111/jnc.15120.
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.
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.
Stamberger H, Nikanorova M, Willemsen MH, et al. STXBP1encephalopathy. Neurology. 2016;86(10):954-962. doi:10.1212/wnl.0000000000002457.
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.
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.
STXBP1-Related Disorders. Children’s Hospital of Philadelphia. https://www.chop.edu/conditions-diseases/stxbp1-related-disorders Accessed Jan 19, 2021.
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