Loss-of-function mutations of STXBP1 in patients with epileptic encephalopathy.

Epileptic encephalopathy, which commences during early infancy, is a severe epileptic syndrome that manifests as age-dependent seizures and severe developmental delay. The syntaxin-binding protein 1 gene (STXBP1) is one of the genes responsible for epileptic encephalopathy. We conducted a cohort study to analyze STXBP1 in 42 patients with epileptic encephalopathy. We identified four novel mutations: two splicing mutations, a frameshift mutation, and a nonsense mutation. All of these mutations were predicted to cause loss-of-function. This result suggests loss-of-function is a common mechanism underlying STXBP1-related epileptic encephalopathy. The four patients showed epileptic features consistent with STXBP1-related epileptic encephalopathy, but showed variable radiological findings, including brain volume loss and myelination delay.

Yamamoto T ，Shimojima K ，Yano T ，Ueda Y ，Takayama R ，Ikeda H ，Imai K ... -  《-》

Epileptic patients with de novo STXBP1 mutations: Key clinical features based on 24 cases.

Mutations in the syntaxin binding protein 1 gene (STXBP1) have been associated mostly with early onset epileptic encephalopathies (EOEEs) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography (EEG) features associated with STXBP1-related epilepsies to orient molecular screening. We screened STXBP1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging (MRI) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP1 found using array comparative genomic hybridization (CGH). We found a mutation of STXBP1 in 22 patients and included 2 additional patients with a deletion including STXBP1. In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression-burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%. Our data confirm that STXBP1 mutations are associated with neonatal-infantile epileptic encephalopathies. The initial key features highlighted in the cohort of early epileptic patients are motor seizures either focal or generalized, abnormal initial interictal EEG, and normal head growth. In addition, we constantly found an ongoing moderate to severe developmental delay with normal head growth. Patients often had ongoing ataxic gait with trembling gestures. Altogether these features should help the clinician to consider STXBP1 molecular screening.

Di Meglio C ，Lesca G ，Villeneuve N ，Lacoste C ，Abidi A ，Cacciagli P ，Altuzarra C ，Roubertie A ，Afenjar A ，Renaldo-Robin F ，Isidor B ，Gautier A ，Husson M ，Cances C ，Metreau J ，Laroche C ，Chouchane M ，Ville D ，Marignier S ，Rougeot C ，Lebrun M ，de Saint Martin A ，Perez A ，Riquet A ，Badens C ，Missirian C ，Philip N ，Chabrol B ，Villard L ，Milh M ... -  《-》

STXBP1-related encephalopathy presenting as infantile spasms and generalized tremor in three patients.

Dominant mutations in the STXBP1 gene are a recently identified cause of infantile epileptic encephalopathy without metabolic and structural brain anomalies. To date, 25 patients with heterozygous mutation or deletion of STXBP1 have been reported. A diagnosis of early infantile epileptic encephalopathy with suppression-burst (Ohtahara syndrome) was made in most of them, with infantile spasms and nonsyndromic infantile epileptic encephalopathy being the diagnosis in other patients. Although the phenotypic spectrum of STXBP1-related encephalopathy is emerging with evidence suggesting the relatively frequent involvement of this gene in infantile epileptic encephalopathies, accurate clinical descriptions of patients are still necessary to delineate this entity. The sequence of the STXPB1 gene was analyzed in 29 patients with early onset syndromic or nonsyndromic infantile epileptic encephalopathy without brain magnetic resonance imaging (MRI) anomalies and with normal chromosomal and metabolic checkup. Another patient with a complex phenotype was analyzed by comparative genomic hybridization (CGH) array. From the studied series, 2 of 29 patients were found to carry a de novo heterozygous mutation in STXBP1. One patient carried the recurrent p.Arg406His mutation and the other an insertion of 10 bases leading to a premature termination codon. CGH array experiment detected a deletion of 3-3.5 Mbp in the third patient with infantile epileptic encephalopathy and nail malformations. All three had infantile spasms associated with partial seizures that responded to antiepileptic drug therapy. Intellectual abilities were severely impaired in all of them. Generalized tremor was the main neurologic striking feature in the three patients, with one of them further displaying unilateral akinetic-hypertonic syndrome. Mutations in STXBP1 are relatively frequent in patients with infantile epileptic encephalopathies. STXBP1-related encephalopathy may present as drug-responsive infantile spasms with focal/lateralized discharges. Generalized tremor appearing after the first year of life may be a clue to the diagnosis in some patients.

Mignot C ，Moutard ML ，Trouillard O ，Gourfinkel-An I ，Jacquette A ，Arveiler B ，Morice-Picard F ，Lacombe D ，Chiron C ，Ville D ，Charles P ，LeGuern E ，Depienne C ，Héron D ... -  《-》

A novel mutation in STXBP1 gene in a child with epileptic encephalopathy and an atypical electroclinical pattern.

Romaniello R ，Zucca C ，Tenderini E ，Arrigoni F ，Ragona F ，Zorzi G ，Bassi MT ，Borgatti R ... -  《-》

[Clinical and genetic characteristics of children with STXBP1 encephalopathy].

Cao JJ ，Ji XN ，Mao YY ，Zhang PP ，Liu WT ，Zhang HZ ，Ding N ，Chen Q ... -  《-》