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 testing are possible.
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