STXBP1 syndrome is a genetic disorder with a significant impact on neurodevelopment. The STXBP1 gene is involved in the regulation of exocytosis processes, that is, with the mechanisms that control the synapse. More specifically, it is involved in neurotransmission. The syntaxin binding protein, also known as Munc18-1, binds syntaxin to form a complex that regulates the release of neurotransmitters from synaptic vesicles.1–3

Mutations in the STXBP1 gene were first described in 2008 in patients with Ohtahara syndrome, also known as early infantile epileptic encephalopathy.4 The clinical manifestations described in these patients included very early onset epilepsy, motor deficits and psychomotor retardation. The STXBP1 gene has also been associated with various epileptic syndromes, such as West syndrome, malignant migrating partial seizures of infancy, Dravet syndrome, severe early myoclonic encephalopathy, Rett syndrome with or without seizures, the combination of autism and epilepsy or epileptic dyskinetic encephalopathy.5 With the advances in genetic testing, the clinical spectrum of this gene has been progressively widening. In a sample of children with early infantile epileptic encephalopathy without Ohtahara or West syndrome, Deprez et al.6 found mutations in the STXBP1 gene in 10% of the patients. Also, mutations in this gene have been found in a significantly higher proportion of individuals with autism spectrum disorder (ASD) compared to the general population.7

Although epilepsy seemed a defining characteristic of the syndrome, there has been an increasing number of cases reported in the literature of mutations in the STXBP1 gene in individuals that never had seizures. Hamdan et al.8 analysed a sample of patients with nonsyndromic intellectual disability and found a mutation in the STXBP1 gene in 1 individual aged 21 years that had never had epilepsy. Later on, there have been other reports of patients with movement disorders and intellectual disability that had mutations in the STXBP1 gene in the absence of epilepsy,9 which has further broadened the clinical picture of STXBP1 syndrome. Although mutations in this gene were initially considered one of the main causes of early-onset epileptic encephalopathy, subsequent studies have demonstrated that epilepsy is just one manifestation within a broad constellation of symptoms with a heterogeneous expression. Thus, STXBP1 syndrome is a neurodevelopmental disorder rather than an epileptic encephalopathy.10–12

The differential diagnosis must include other diseases associated with epileptic features with early onset, such as pyridoxine-dependent epilepsy, pyridoxamine 5′- phosphate oxidase (PNPO) deficiency, cerebral folate deficiency or glucose transporter type 1 (GLUT1) deficiency.13

Descriptions of the clinical presentation of individuals with STXBP1 syndrome suggest that when epilepsy is present, it has a very early onset. The mean age at onset of seizures is 6 weeks post birth, and the range goes from the first day of life to 12 years.10 Controlling the seizures is usually challenging at the beginning, although outcomes on this aspect are quite heterogeneous. Published studies are consistent in reporting a favourable outcome in most individuals with mutations in this gene, although a small proportion continue to have frequent seizures.4–6,12 Stamberger et al.10 found that in a sample of 147 patients, nearly half (43.8%) stopped experiencing seizures between 1 month and 4 years of age, with the median age at resolution of 8 months. However, 28.7% of the sample continued to have frequent seizures (more than once a week despite treatment). These authors also found recurrence of epilepsy after a long period of remission in 6 of the patients under study. All patients had intellectual disability, generally requiring considerable support. Cognitive impairment was limited to learning disabilities in only 1 case.

Nearly half of the individuals identified by Stamberger et al.10 were able to take a few steps independently. They developed this skill between ages 14 months and 6 years. Fifteen percent of the patients had some ability to communicate verbally, and ASD was present in 17% of the sample. The authors also described a high frequency of movement disorders, such as hypotonia, ataxia, tremors, spasticity, dyskinesia and dystonia.10

The variability in the phenotype of STXBP1 disorders may lead to their underdiagnosis.11 The analysis of a birth cohort spanning 10 years in Denmark found a prevalence of 1/91 862.10 To date, there are no data on the prevalence of STXBP1 syndrome in Spain, but based on the current literature it appears that this syndrome may be associated with a considerable number of neurodevelopmental disorders manifesting with movement problems and epileptic features.

The aim of our study was to describe the characteristics of the population of individuals known to have STXBP1 syndrome in Spain and their diagnostic needs. The description of the features of this syndrome and its early clinical manifestations may help identify new cases and reduce the delay in diagnosis.

At the beginning of the study period, there were 20 individuals in Spain diagnosed with STXBP1 syndrome that had made contact with the STXBP1 Association, either of their own initiative or after being referred by the department that made the diagnosis. We sent the families information about the study as well as an informed consent form in case they chose to participate. The information presented in this article has been drawn from a larger study whose aim is to describe the characteristics of this collective in Spain, define its needs and propose priority guidelines to improve the quality of life of affected individuals and their families. Of the 20 families that we invited to participate, 17 accepted (85%). Once we obtained the informed consent forms, we requested information from the families through 3 online questionnaires sent at 3 different time points. These questionnaires were completed on an anonymous basis by one or both parents. The questionnaires collected information on the individual with STXBP1 syndrome, the characteristics of the family, and the personal experiences and perception of different processes and aspects of life as an individual with STXBP1 syndrome or a family member.

STXBP1 syndrome manifests early in life and has a significant impact on neurodevelopment. Early diagnosis is essential to provide the necessary support, avoid unnecessary tests and counsel families on how to manage the necessary resources. To promote the dissemination of information on this syndrome and its early detection, we have gathered information from 17 families of affected individuals in Spain on the characteristics of patients with STXBP1 syndrome and the diagnostic process. The methods used in the study pose limitations, as we only have data from 17 families and we obtained the information directly from the families without comparing it to medical records. However, taking into account the low incidence of this syndrome and that these patients received the diagnosis relatively recently, we believe that the collected information may provide relevant data and a starting point for further research.

We now proceed to summarise the needs identified in the study in relation to the diagnostic process.

First, the number of cases of STXBP1 syndrome detected in Spain to date is much lower than expected based on currently available prevalence data. Taking into account the distribution of the population in Spain and the provinces where the identified affected individuals reside, it is evident that detection is associated with the accessibility of necessary tests or diagnostic services, and not to the actual incidence of the syndrome. The unequal geographical distribution of diagnosed cases suggests significant underdiagnosis in regions that do not have specialised services or facilities equipped to perform the necessary genetic tests. On the other hand, there is a growing knowledge of the phenotypic expression of changes in the STXBP1 gene, such as the occurrence of cases of mutations that never manifest with epileptic features.9 Thus, we expect that as more information becomes available and diagnostic tests more accessible, the number of cases identified in Spain will increase substantially. Although at present STXBP1 syndrome is considered a very rare disease, the emerging evidence suggests that these mutations could be involved in many cases of intellectual disability, movement disorders and epileptic encephalopathies of unknown cause.

At present, the delay in diagnosis is very high. Diagnosis is most delayed in cases presenting without epileptic seizures, spasms or abnormal movements serving as early warning signs of a disorder. Developmental stagnation and motor abnormalities could be the initial manifestations to prompt an early assessment of symptoms that would in turn guide the clinician to order the necessary genetic tests.

Most individuals with STXBP1 syndrome have experienced or will develop seizures at some point in life. Further research on the control of epilepsy is essential, on one hand to achieve control of seizures in refractory cases, and, on the other, to reduce intake of medication to the minimum possible. Given that in some cases epilepsy recurs after a long period of remission, research on the biological and behavioural markers that may provide information on the clinical course of epilepsy is also essential. This would help avoid the use of unnecessary medication or, on the other side of the spectrum, maintain treatment when there is risk of recurrence.

The characteristics of individuals with STXBP1 syndrome in our sample evince the substantial variation in the need for support in different areas. Further research is necessary in relation to communication and language development. Although previous studies have reported that 17% of individuals with STXBP1 syndrome also have ASD, only 1 person in our sample had this additional diagnosis. However, most affected individuals in our sample exhibited a limited communicative intent, and people in their environment needed to interpret their intentions and wishes. Although this aspect requires in-depth research, it is not clear that this lack of intent is due solely to cognitive or motor difficulties. On the contrary, these difficulties may mask specific disturbances in communication requiring further exploration. Consequently, it is essential that this dimension is investigated and to develop intervention strategies and information and technology systems to safeguard the right to communication of individuals with STXBP1 syndrome.

There is also little evidence on the efficacy of different interventions aimed at promoting motor development in affected individuals.

Improvements in the detection and diagnosis of STXBP1 syndrome and research on molecular, pharmacological and behavioural therapies in its management are essential to improve the quality of life of affected individuals and their families.

The authors have no conflicts of interest to declare.