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A recent study delved into the epilepsy and developmental patterns of STXBP1-related disorders, showing distinct trajectories and treatment insights for this common genetic epilepsy disorder.
Ingo Helbig, MD
Credit: CHOP
In a recent retrospective, cross-sectional study, investigators delineated epilepsy and developmental trajectories among patients with STXBP1-related disorders using standardized measures, providing a framework to interpret future therapeutic strategies and educate trial design.1
Onset of epilepsy significantly differed across seizure types in patients with STXBP1-related disorder (n = 162), with a 90% cumulative onset for infantile spasms by 6 months and focal-onset seizures by 27 months of age. Investigators also observed that epilepsy histories (n = 1281) diverged between variant subgroups in the first 2 years of life. Patients with protein-truncating variants and deletions in STXBP1 (n = 39) had a higher risk of infantile spasms between 5 and 6 months followed by seizure remission. In addition, patients with missense variants (n = 30) showed an increased risk for focal seizures and ongoing seizures following the first year.
“This study is another major milestone in our commitment to patients and families diagnosed with STXBP1-related disorders,” senior author Ingo Helbig, MD, codirector of the Epilepsy Neurogenetics Initiative (ENGIN) and clinical director of Children’s Hospital of Philadelphia (CHOP) Center for Epilepsy and Neurodevelopmental Disorders (ENDD), said in a statement.2 “We identified treatment windows and outcome measures that will help us interpret the success of clinical trials for these disorders. Most importantly, we were able to demystify the complex disease pattern in STXBP1 disorders to make these conditions ready for clinical trials.”
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Published in Brain, researchers investigated cumulative patient-years of seizure and developmental histories in patients with STXBP1-related disorders, characterized by a dynamic pattern of seizures in the first year of life and high variability in neurodevelopmental trajectories in early childhood. Investigators mapped the developmental outcomes of the patients using milestone acquisition data in addition to standardized assessments including the Gross Motor Function Measure-66 Item Set and the Grasping and Visual-Motor Integration subsets of the Peabody Developmental Motor Scales.
During the first 5 years of life, the quantification of end points showed high variability with emerging stratification between clinical subgroups. Investigators observed an earlier epilepsy onset associated with lower developmental abilities, most prominently in the assessment of gross motor development and expressive communication. In addition, authors observed that patients with neonatal seizures or early infantile seizures followed by seizure offset by 12 months of age showed more predictable seizure trajectories in early to late childhood compared with patients who had more severe seizure presentations, including those with refractory epilepsy through the first year.
Over time, the characterization of antiseizure medication response showed an age-dependent response. Authors noted that phenobarbital, levetiracetam, topiramate and adrenocorticotropic hormone performed well in reducing seizures in the first year of life. In long-term seizure management, authors observed clobazam and the ketogenic diet displayed strong efficacy in seizure reduction over 1 year of life. In virtual clinical trials assessing seizure frequency, findings demonstrated a wide range of success probabilities across the age span with the highest probability in early childhood between 1 year and 3.5 years.
All told, the outcomes for early-to-late childhood in the study likely included over-representation of a more severely affected subgroup for which the data were available to use. Although the study showed that clinical heterogeneity had an association with markers of disease severity, investigators were not able to explore the effect of genomic background and variation contributing to the wide range of outcomes.3 Additionally, authors noted that families of patients with STXBP1 identified clinical features including gastrointestinal and respiratory symptoms that are underrepresented in the current literature and may be used as additional end points with measures for tremor and ataxia in STXBP1.4
“By assessing epilepsy trajectories and developmental endpoints across the age span, this study helps establish an important baseline to help inform personalized treatment options and enable us to meaningfully interpret future therapeutic strategies,” lead author Julie Xian, a data scientist with the ENGIN and the University of Pennsylvania and CHOP ENDD, said in a statement.2
