Etiology
STXBP1-RD are autosomal dominant disorders caused by de novo, heterozygous mutations in STXBP1 gene.
The STXBP1 gene is located on chromosome 9q34.1 and encodes the synaptic protein STXBP1, also known as Munc18-1. This protein plays a critical role in the release of neurotransmitter from synaptic vesicles and the communication between neuronal cells .
Munc18-1 was known and studied since late 1990s, but it hadn’t been linked to a disease until 2008, when Saitsu et al reported of an association between STXBP1 mutations and a severe early-onset epileptic encephalopathy. The first diagnoses were characterized by a strong bias towards severe, early-onset epilepsy; subsequently, patients with STXBP1 mutations have been reported also with late-onset epilepsy, milder phenotypes, or no epilepsy at all. The first comprehensive description of a large cohort of patients was reported by Stamberger et al in 2016 and the condition was named STXBP1 encephalopathy.
Known disease causing STXBP1 variants span across the whole gene and can be of any type (protein truncating, missense, frameshift). Although recurrent variants are reported, there no clear mutational hotspots.
Variants usually result in inadequate (functional) STXBP1 protein, or haploinsufficiency. Although, it’s been hypothesized that some variants might also create misfolded proteins and accumulation.
Incidence and prevalence
The estimated incidence of STXBP1-RD is between 1:30.000 and 1:100.000. More than 500 individuals worldwide have been reported in literature to date, but the prevalence is most likely higher because of selection bias towards patients with more severe phenotypes in research papers.
Diagnosis
STXBP1-RD are suspected in individuals with intellectual disability and developmental delay, especially if associated with early onset epilepsy. The diagnosis is confirmed by genetic testing with the identification of a pathogenic variant in the STXBP1 gene.
STXBP1-RD associated variants are typically de novo heterozygous variants. Parental mosaicism has been reported in few patients, and there has been one report of a homozygous mutation inherited from unaffected parents (although with a different disease mechanism, in this case it is suspected to be gain of function).
Age of onset and symptoms at presentation
The first symptoms are early onset epileptic seizures most of the time. Seizures present in the first year of life in most of the patients. More rarely, seizures can have a later onset, after the 1st year. Focal-onset motor seizures, generalized-onset motor seizures and epileptic spasms are the most frequently reported seizure types at onset.
Most of the patients present developmental delay before 12 months of age. For some patients, developmental delay may be the first symptom, preceding seizure onset. A minority of patients never develop epilepsy.
How do seizures change over time?
Epilepsy associated with STXBP1-RD is variable in seizure types, frequency, and outcomes.
During the neonatal period, seizures present mostly as focal onset motor seizures and/or epileptic spasms. They are usually very frequent and can appear in clusters. A clinical diagnosis of Ohtahara syndrome is made in some patients.
Epileptic spasms are common in infancy, together with generalized and focal onset motor seizures. Absence seizures have been reported as well. Some patients have a clinical presentation compatible with West syndrome. While a third of patients become seizure-free in the first year, most of them develop drug-resistant epilepsy.
Motor seizures are most frequent in childhood, and some children develop Lennox-Gastaut syndrome. Seizure frequency decreases in some patients, and seizure freedom does occur in some. Relapses of seizures do however occur frequently.
Patients can have paroxysmal non-epileptic movement disorders that can be difficult to distinguish from epileptic seizures, therefore video-EEG is mandatory to make this distinction.
In most patients with epilepsy, seizures persist at adult age; a third of patients may experience prolonged seizure-freedom in adolescence with seizure recurrence at later age. Few patients are seizure-free in adulthood.
EEG features
The EEG pattern is mainly characterized by the presence of focal/multifocal interictal epileptiform discharges and (focal) slowing activity. In infancy, specific EEG patterns such as burst suppression or hypsarrhythmia are seen in some patients.
Development and function
Neurodevelopment and cognitive function are compromised in all individuals with STXBP1-RD. This impairment is mostly severe, however developmental trajectories and outcomes can be variable.
A number of patients present with neurological abnormalities during neonatal period (e.g. hypotonia) and hardly achieve head control. Gross and fine motor developmental is typically delayed and the functional outcome is variable. Some patients can achieve walking ability, with or without assistance, while others are or become wheelchair-bound.
Language development is usually severely compromised, with most of the individuals not developing any speech and having very limited communication ability (few words or simple sentences).
All individuals are partially or completely dependent for most activities of daily living.
Some patients may experience episodes of developmental stagnation or regression during childhood and adolescence and lose some motor or communication skills. Further research is needed to identify triggers for these periods of regression.
Many patients with STXBP1-RD exhibit behavioral problems and problems with social interaction, including autistic features. These behavioral problems can persist into adulthood and may require medical treatment.
Neurological examination
Patients present with a range of neurological symptoms. Hypotonia is very common at onset, evolving in spasticity later.
Gate abnormalities are present in most individuals able walk, including an ataxic or broad base gate and postural abnormalities.
Abnormal movements are very frequent, sometimes difficult to distinguish from seizures, therefore video-EEG is necessary to dissect the nature of the abnormal movements. Tremor is frequently reported and can range in severity, and may be debilitating. The tremor is mostly action/intentional and may have myoclonic features or more consistent with tremor like subcortical myoclonus. Dystonia or choreic movements are frequently present. Stereotypies are frequent, involving hands and/or head, such as “figure-of-8” head movements.
Sensory systems are usually intact in individuals with STXBP1-RD, although some might present altered tolerance to sensory stimuli.
Comorbidities and life expectancy
Sleep disturbances are frequently reported in individuals with STXBP1-RD, mainly consisting in difficulty in falling asleep and recurrent awakenings during the night. Gastrointestinal symptoms, including gastro-esophageal reflux and problems with intake are seen regularly, and some patients require percutaneous endoscopic gastrostomy for feeding. Skeletal problems like scoliosis, foot deformities, and hyperlaxity can be present and influence motor function.
There are no data on life expectancy in STXBP1-RD to date. Individuals with STXBP1-RD can live until late adulthood (oldest patient reported is 60-year-old), although different complications may arise at any age depending on the epilepsy course, functional status, and comorbidities. Early mortality has been reported in few individuals, though exact data on the mortality rate in STXBP1-RD are missing.
Treatment
Treatment is symptomatic and requires a multi-disciplinary approach.
Anti-seizure medications have different efficacy, with no clear superiority of a drug regimen, and poly-therapy is often needed to control seizures. There are retrospective studies that mention a good effect of levetiracetam or ketogenic diet, however we lack appropriate studies to proof this. No specific recommendations can be made for now, and antiseizure therapeutic strategies need to be evaluated on individual bases in each case.
Habilitation therapies are recommended to maximize the developmental potential of each individual. Physical therapy, psychomotor, speech, and occupational therapies can be beneficial at all ages and need to be considered on a case-to-case basis, depending on the functional status of the patient.
Follow-up evaluations
Review the impact of seizures, drugs & comorbidities on
Day-to-day activities; nutrition and fluid intake; mental and physical health; cognition and development; behavior; sleep; autonomy/independence; overall well-being and quality of life of the patient and the caregivers.
Individualized emergency protocols
The recommended emergency protocols apply, as no disease-specific protocols exist. Specific individual features of the patient must be taken into account.
Provide patient/carer with
- Individualized emergency protocol for seizures
- SUDEP risk management
- Indications for habilitation and support (neuropsychological evaluation, physical therapy, speech therapy, support for intellectual development)
- Genetic counselling
- Patient, carer & employer support requirements (neuropsychological evaluation, guidance, potential psychiatric support)