title: STXBP1-related encephalopathy presenting as infantile spasms and generalized tremor in three patients.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinical Genetic Unit Pitié-Salpêtrière Hospital, AP-HP, Paris, France. cyril.mignot@psl.aphp.fr
authors.forename: Cyril
authors.initials: C
authors.lastname: Mignot
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Moutard
authors.forename: Oriane
authors.initials: O
authors.lastname: Trouillard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gourfinkel-An
authors.forename: Aurélia
authors.initials: A
authors.lastname: Jacquette
authors.forename: Benoit
authors.initials: B
authors.lastname: Arveiler
authors.forename: Fanny
authors.initials: F
authors.lastname: Morice-Picard
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: Catherine
authors.initials: C
authors.lastname: Chiron
authors.forename: Dorothée
authors.initials: D
authors.lastname: Ville
authors.forename: Perrine
authors.initials: P
authors.lastname: Charles
authors.forename: Eric
authors.initials: E
authors.lastname: LeGuern
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use; D001921:Brain / Q000503:physiopathology; D004569:Electroencephalography; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D051938:Munc18 Proteins / Q000235:genetics*; D016254:Mutagenesis, Insertional / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013036:Spasms, Infantile / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D014202:Tremor / Q000150:complications / Q000235:genetics* / Q000503:physiopathology
chemical_list: D000927:Anticonvulsants; D051938:Munc18 Proteins; C497937:STXBP1 protein, human