STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern.

De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects. STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells. A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells. Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.

Saitsu H ，Kato M ，Okada I ，Orii KE ，Higuchi T ，Hoshino H ，Kubota M ，Arai H ，Tagawa T ，Kimura S ，Sudo A ，Miyama S ，Takami Y ，Watanabe T ，Nishimura A ，Nishiyama K ，Miyake N ，Wada T ，Osaka H ，Kondo N ，Hayasaka K ，Matsumoto N ... -  《-》

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 ... -  《-》

Early epileptic encephalopathies associated with STXBP1 mutations: Could we better delineate the phenotype?

STXBP1 (MUNC18.1), encoding syntaxin binding protein 1, is a gene causing epileptic encephalopathy. Mutations in STXBP1 have first been reported in early onset epileptic encephalopathy with suppression-bursts, then in infantile spasms and, more recently, in patients with non syndromic mental retardation without epilepsy. We analyzed clinical evolution and brain magnetic resonance imaging in 7 patients (6 females, 1 male) with early onset epileptic encephalopathies associated with STXBP1 mutations. We documented a peculiar brain MRI aspect characterized by frontal hypoplasia and a thin and dysmorphic corpus callosum. The course of the epilepsy was relatively benign. These clinical and neuroradiological features could orient the clinician in selecting patients' candidate to genetic testing for STXBP1 gene.

Barcia G ，Chemaly N ，Gobin S ，Milh M ，Van Bogaert P ，Barnerias C ，Kaminska A ，Dulac O ，Desguerre I ，Cormier V ，Boddaert N ，Nabbout R ... -  《-》

Neonatal suppression-burst without epileptic seizures: expanding the electroclinical phenotype of STXBP1-related, early-onset encephalopathy.

Mastrangelo M ，Peron A ，Spaccini L ，Novara F ，Scelsa B ，Introvini P ，Raviglione F ，Faiola S ，Zuffardi O ... -  《EPILEPTIC DISORDERS》