Researchers at the Department of Molecular Genetics, University of Antwerp, and other centers in Belgium, The Netherlands, and Melbourne, Australia, analyzed the clinical phenotypes associated with STXBPl mutations in a cohort of 106 patients with unexplained early-onset epileptic encephalopathies. Nine patients were diagnosed with Ohtahara syndrome, 32 had West syndrome, 14 had migrating partial seizures of infancy, and 2 patients had early myoclonic encephalopathy (EME). The term, early-onset epileptic encephalopathy (EOEE) was used for the remaining 49 patients with an undefined epileptic syndrome. Disease-causing mutations were indentified in six EOEE patients (5.7%). Age of seizure-onset ranged between 3 days and 4.5 months. None had Ohtahara syndrome, recently attributed to heterozygous mutation in STXBPl gene, and 1 (3%) had West syndrome. In contrast, 5 (10.2%) of the patients with EOEE had STXBPl mutations. The clinical phenotype of EOEE was a seizure onset at 3 days to 10 weeks, seizure type tonic, clonic, myoclonic, partial or epileptic spasms, psychomotor retardation, normal head growth, EEG at seizure onset showing focal or bilateral synchronous discharges, and hypsarrhythmia and West syndrome diagnosed in 3 patients by 5 month of age. Ataxia developed in 3, and 3 had profound retardation with hypotonia or dyskinetic movements. [1]

COMMENT. Summarizing the phenotypic profile of infants with STXBP1 mutations: an early-onset epilepsy within the first 5 months of life, beginning as Ohtahara syndrome or as EOEE, frequent evolution to West syndrome, severe mental retardation, and neurologic deficits with dyskinesia.

Mutations in STXBP1 occur in patients with Ohtahara and West syndromes and are also present in 10% of patients with undefined early-onset epileptic encephalopathies without the burst-suppression EEG, typical of Ohtahara syndrome. The authors recommend STXBP1 mutation analysis in the evaluation of infants with unexplained EOEE. Other known genes for epileptic encephalopathies include SCN1A, ARX, CDKL5, and PCDH19. Neurodegeneration and mental retardation associated with STXBP1 are presumed to be an intrinsic property of the gene mutations, and are independent of the severity of the epilepsy and response to antiepileptic drugs.

Genetic causes of epileptic syndromes will be added to the clinical and EEG classifications of the epilepsies as a result of expanding molecular research. Holland KD and Hallinan BE of Cincinnati, in an editorial [2], recommend genetic testing for infants with unexplained epileptic encephalopathies. A gene mutation diagnosis may obviate the necessity for exhaustive and invasive investigations and lead to more effective therapy. Dravet syndrome, an encephalopathy caused by mutations in the SCN1A sodium channel gene, is exacerbated by sodium channel AEDs (eg carbamazepine) [3]. Seizures caused by STXBP1 mutations respond to vigabatrin and are resistant to other AEDs. (Deprez L et al. 2010).