STXBP1 mutations are associated with early onset epileptic encephalopathy (EOEE). Our aim was to explore the phenotype spectrum, clinical treatment and prognosis of STXBP1-related encephalopathy (STXBP1-E). Clinical and genetic data were collected from 10 patients with STXBP1 mutations. These patients were examined and diagnosed from 2015 to 2021 at the Pediatric Department of Qilu Hospital. Blood samples were collected and sequenced by next generation sequencing and Candidate pathogenic variants were identified using Sanger sequencing in all family members. All of the patients showed severe epilepsy, varying degrees of intellectual disability and delayed motor. The patients developed multiple seizure types and abnormal electroencephalography (EEG) results at onset, and focal seizures were the most frequent seizure type. Among the patients, 2 were diagnosed with Ohtahara syndrome, 2 patient was diagnosed with West syndrome. The other 6 patients could not be diagnosed with any specifically recognized epilepsy syndrome. Five of the 10 patients had a history of fever with seizures, 4 of whom had eliminated intracranial infection according to the results of cerebrospinal fluid (CSF) examinations, and the other patient was diagnosed with anti-myelin oligodendrocyte glycoprotein (MOG) -associated encephalitis. We identified one patient with a complete deletion of STXBP1 and 9 patients with de novo heterozygous mutations of STXBP1. Among those mutations, 4 were novel (c.56°C > T, c.1315A > T, c.751G > C, and c.554_559del), and 5 had been previously reported [c.364C > T, c.569G > A (2 cases), c.748C > T, and c.1651C > T]. For 8 of our patients, different combinations of anti-seizure medications (ASMs) led to seizure freedom. One patient with MOG antibodies in his serum obtained a poor therapeutic effect from the traditional ASMs treatment, so he had to achieve seizure-free status through vagus nerve stimulation (VNS), which had little effect on his psychomotor ability. Fortunately, in one case, patient psychomotor ability was improved through VNS. Our study shows that STXBP1 screening should be considered in patients with neonatal seizures with intellectual disability, and frequent seizures with fever should also be considered with the STXBP1 mutation when intracranial infection is eliminated. VNS has expanded outcome measures to include behavioral and developmental function as well as seizure control.

We aimed to investigate the effects of ketogenic diet (KD) and modified Atkins diet (MAD) in patients with epileptic encephalopathy, caused by the STXBP1 (syntaxin-binding protein 1) gene mutation. We retrospectively evaluated the data of patients with STXBP1-related epileptic encephalopathy who were started on either KD or MAD between January 1, 2005, and June 30, 2021, in Severance Children's Hospital. Twelve patients were examined. The median age of seizure onset was 1.5 months [interquartile range (IQR): 0-3] with a median age of dietary therapy initiation at 4.5 months (IQR: 3.0-9.3) and a median diet duration of 6.5 months (IQR: 2.8-13.3). The patients had various epilepsy syndromes: nine (75 %) patients had early infantile developmental and epileptic encephalopathy, two (16.7 %) had infantile epileptic spasms syndrome, and one (8.3 %) had developmental and epileptic encephalopathy. Three patients (25 %) were definite KD responders who achieved seizure freedom within the median of 2 months from KD initiation and remained seizure-free for a median of 36 months (IQR: 29.5-60.0). One patient (8.3 %) was a possible KD responder, seizure-free with KD initiation and steroid therapy while 8 were non-responders (66.7 %). The definite KD responders shared similar clinical characteristics as the rest, except that there were significantly more patients that had seizure onset at ≥ 6 months (p = 0.045) in the definite KD responder group. We demonstrated dietary therapy was highly effective for some patients with STXBP1-related epileptic encephalopathy, especially those with later onset.

Syntaxin binding protein 1 (STXBP1) plays an important role in the release of synaptic vesicles. STXBP1-related encephalopathy is a brain dysfunction caused by STXBP1 variation. Levetiracetam (LEV) exerts antiepileptic effects by binding to synaptic vesicle protein 2A (SV2A). This study aimed to analyze the prognosis of LEV treatment of STXBP1 encephalopathy (STXBP1-E) and the correlation among genotype, phenotype, and LEV efficacy. Patients with pathogenic STXBP1 variants were collected from multiple centers, and their clinical history, video electroencephalogram (vEEG) characteristics, imaging examination data, and anti-seizure medication (ASM) history were systematically analyzed. The ASMs related to the prognosis were explored. Forty patients with STXBP1-E were enrolled in this study. The detailed ASM usage of 37 patients was recorded without intervening in ASM selection. At the endpoint of six months treatment, the results of Fisher's exact test showed that in all ASMs, LEV affected the prognosis of patients with STXBP1-E. LEV was effective in improving the partial remission rate but did not achieve seizure freedom. However, LEV monotherapy could achieve seizure freedom in patients with other early-onset epileptic and encephalopathy. For refractory West syndrome (WS) or Ohtahara syndrome (OS), LEV combined with other ASMs could improve the seizure remission rate. LEV increased the seizure reduction rate and improved the vEEG characteristics in patients with STXBP1-E, but not seizure freedom. LEV combined with other ASMs could increase the seizure reduction rate, especially for refractory WS or OS. Thus, LEV could be considered after identifying the pathogenicity of STXBP1 variants.

The phenotypic spectrum of STXBP1-related encephalopathy ranges from infantile epileptic encephalopathy to intellectual disability with nonsyndromic or absent epilepsy. Although being frequently reported, the tremor associated with STXBP1 has not been fully characterized to date. The aim of our study was to describe it. We recruited patients with intellectual disability due to STXBP1 variants, regardless of their epileptic phenotype, who had tremor at examination and who underwent neurophysiological testing including polymyographic registration of upper limbs muscles activity at rest, during posture maintenance and action. Six patients met the inclusion criteria over four years. Clinically, all had a postural and action distal tremor increased by emotions. Neurophysiological recordings showed a specific myoclonus pattern and were highly suggestive of a subcortical generator. The tremor-like observed in STXBP1 encephalopathy is due to a subcortical pseudo-rhythmic myoclonus.