Clinical Description
Since the original description of STXBP1 encephalopathy with epilepsy in five individuals with Ohtahara syndrome [Saitsu et al 2008], approximately 200 affected individuals have been reported [Vatta et al 2012, Allen et al 2013, Tucker et al 2014, Ehret et al 2015, Kwong et al 2015, Dilena et al 2016, Guacci et al 2016, Helbig 2016, Marchese et al 2016]; see also Di Meglio et al [2015], Allen et al [2016], Nambot et al [2016], Yamamoto et al [2016], Lopes et al [2016] and references therein.
All affected individuals have developmental delay, cognitive dysfunction, or intellectual disability. The majority of affected individuals have presented with seizures.
Developmental delay, cognitive dysfunction, or intellectual disability, present in all individuals with STXBP1 encephalopathy with epilepsy, range from moderate to severe in more than 90% of individuals.
Seizures are the second most common clinical feature in STXBP1 encephalopathy with epilepsy. Although the majority of affected individuals presented with seizures, ten (6%) had no history of seizures [Hamdan et al 2011, Rauch et al 2012, Gburek-Augustat et al 2016, Stamberger et al 2016].
Onset of seizures ranges from ages six hours to 13 years [Milh et al 2011, Di Meglio et al 2015]. About half of affected children had seizures in the neonatal period. Approximately 40% had seizures between ages one month and 12 months. In fewer than 10% of affected individuals, seizure onset was after age one year.
Seizure types include infantile spasms and generalized tonic-clonic, generalized clonic, generalized tonic, myoclonic, atonic, and absence seizures. More than 60% of affected individuals had more than one seizure type during their lifetime.
Focal seizures were reported in about 10% of affected individuals.
Epilepsy syndromes
West syndrome (OMIM
308350) is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG.
Early myoclonic epileptic encephalopathy, characterized by myoclonic seizures and burst suppression pattern in sleep on EEG, was identified in two individuals with
STXBP1 encephalopathy with epilepsy [
Saitsu et al 2012,
Kodera et al 2013].
Dravet syndrome (OMIM
607208) is characterized by fever-induced refractory seizures with age of onset usually within the first year of life. EEG patterns typically show generalized spike-wave activity as seizures progress. Three of 80 individuals with Dravet syndrome were identified with
STXBP1 encephalopathy with epilepsy [
Carvill et al 2014].
Lennox-Gaustaut syndrome is characterized by multiple seizure types particularly tonic and myoclonic refractory epilepsy. EEG shows slow background and spike-wave bursts at frequencies less than 2.5 per second. One of 115 individuals with Lennox-Gaustaut syndrome was identified with
STXBP1 encephalopathy with epilepsy [
Allen et al 2013].
Electroencephalography (EEG) abnormalities were reported in the majority of affected individuals.
The two most common EEG abnormalities were burst suppression pattern (42 affected individuals) and hypsarrhythmia (37 affected individuals) [Saitsu et al 2012, Allen et al 2013, Kim et al 2013, Di Meglio et al 2015, Sampaio et al 2015, Allen et al 2016, Guacci et al 2016]; see also Yamamoto et al [2016] and references therein.
Other EEG abnormalities included focal and multifocal discharges, spike-and-slow wave activity, poly-spike waves, theta and delta waves, paroxysmal activity, and low-amplitude fast rhythms. Background activity was frequently described as slow or poorly organized.
Brain magnetic resonance imaging (MRI) was reported in more than 75% of affected individuals. In about half of these individuals, brain MRI showed various abnormalities including diffuse cerebral atrophy, delayed myelination, or thinning of the corpus callosum.
Hypotonia or absence of head control was reported in fewer than 50% of affected individuals.
Movement disorders were observed in fewer than 50 affected individuals.
Ataxia, the most common movement disorder, was either isolated or in combination with other movement disorders including dyskinesia, dystonia, tremor, or choreoathetosis [Campbell et al 2012, Rauch et al 2012, Keogh et al 2015, Mercimek-Mahmutoglu et al 2015, Olson et al 2015, Romaniello et al 2015]; see also Di Meglio et al [2015] and references therein.
Dystonia, the second most common movement disorder, was present in fewer than ten individuals, sometimes occurring in combination with tremor, rigidity, or dyskinesia [Milh et al 2011, Rauch et al 2012, Barcia et al 2013, Di Meglio et al 2015, Keogh et al 2015, Kwong et al 2015, Sampaio et al 2015, Guacci et al 2016, Stamberger et al 2016].
Behavior disorders including autism spectrum disorder, autistic-like features, hyperactivity, or self-aggressive behavior were seen in fewer than 40 affected individuals. Autistic features were the most common behavior disorder [Campbell et al 2012, Allen et al 2013, Weckhuysen et al 2013, Boutry-Kryza et al 2015, Mercimek-Mahmutoglu et al 2015, Romaniello et al 2015, Allen et al 2016]; see also Lopes et al [2016] and references therein.
Other features
Absent thumbnails and hypoplastic second fingernails (1 individual) [
Mignot et al 2011]
Cleft lip and palate, ventricular septal defect, overlapping fingers, small penis (1 individual) [
Saitsu et al 2012]
Cleft lip/palate, umbilical hernia, mild
dysmorphic facial features, dilated renal pelvis, microcephaly (1 individual) [
Nicita et al 2015]