title: CDKL5 and ARX mutations are not responsible for early onset severe myoclonic epilepsy in infancy.
abstract: BACKGROUND
  Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome (DS) is a distinctive epilepsy syndrome often associated with de novo mutations in the SCN1A gene. However, 25-30% patients with SMEI/DS are negative for SCN1A mutation screening, suggesting that other molecular mechanisms may account for these disorders. Given the overlapping and heterogeneous clinical features of CDKL5- and ARX-related epilepsies and SMEI/DS, we postulated that CDKL5 mutations in females and ARX mutations gene in males may be associated with early onset seizures forms of SMEI/DS.
  
  
  METHODS
  Twenty-eight patients with early onset SMEI/DS before 6 months negative for SCN1A mutational screening were selected and screened for mutations in the ARX gene in males (n=14) or the CDKL5 gene in females (n=14).
  
  
  RESULTS
  No mutations in either gene were found except one intronic variation of uncertain pathogenicity in the CDKL5 gene. All patients started seizures at mean age of 3.48 months. Thirteen patients had familial history of epilepsy or febrile seizures. Patients evolved toward refractory epilepsy with generalized tonic clonic seizures (18/28) and myoclonia (23/28) and severe neurological impairment with autistic features (13/28), ataxia (14/28) and spasticity (5/28). No patient ever exhibited infantile spasms, dystonia, or Rett-like features.
  
  
  CONCLUSIONS
  Our results illustrate that mutation screening of ARX and CDKL5 is not effective in patients selected on the basis of clinical signs associated to early onset SMEI/DS. In addition, they might reflect that other phenotypic features associated with CDKL5 mutations (Rett-like features, infantile spasm) or ARX mutations (dystonia, spasticity) are more distinctive.
authors.affiliation: Service de Neurologie Pediatrique, hôpital Necker Enfants Malades, APHP, Université Paris Descartes, Paris, France.
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.forename: Mathilde
authors.initials: M
authors.lastname: Chipaux
authors.forename: Benoit
authors.initials: B
authors.lastname: Girard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Souville
authors.forename: Oriane
authors.initials: O
authors.lastname: Trouillard
authors.forename: Olivier
authors.initials: O
authors.lastname: Dulac
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.forename: Eric
authors.initials: E
authors.lastname: Leguern
authors.forename: Cherif
authors.initials: C
authors.lastname: Beldjord
authors.forename: Thierry
authors.initials: T
authors.lastname: Bienvenu
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004831:Epilepsies, Myoclonic / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D009154:Mutation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D003294:Seizures, Febrile / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: C469264:ARX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human