Dataset Information

Epilepsy Course and Developmental Trajectories in STXBP1-DEE.

ABSTRACT:

Background and objectives

Clinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy.

Methods

Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE.

Results

Forty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course.

Discussion

The disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.

SUBMITTER: Balagura G

PROVIDER: S-EPMC9157582 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Publications

Epilepsy Course and Developmental Trajectories in <i>STXBP1</i>-DEE.

Balagura Ganna G Xian Julie J Riva Antonella A Marchese Francesca F Ben Zeev Bruria B Rios Loreto L Sirsi Deepa D Accorsi Patrizia P Amadori Elisabetta E Astrea Guja G Baldassari Simona S Beccaria Francesca F Boni Antonella A Budetta Mauro M Cantalupo Gaetano G Capovilla Giuseppe G Cesaroni Elisabetta E Chiesa Valentina V Coppola Antonietta A Dilena Robertino R Faggioli Raffaella R Ferrari Annarita A Fiorini Elena E Madia Francesca F Gennaro Elena E Giacomini Thea T Giordano Lucio L Iacomino Michele M Lattanzi Simona S Marini Carla C Mancardi Maria Margherita MM Mastrangelo Massimo M Messana Tullio T Minetti Carlo C Nobili Lino L Papa Amanda A Parmeggiani Antonia A Pisano Tiziana T Pisano Tiziana T Russo Angelo A Salpietro Vincenzo V Savasta Salvatore S Scala Marcello M Accogli Andrea A Scelsa Barbara B Scudieri Paolo P Spalice Alberto A Specchio Nicola N Trivisano Marina M Tzadok Michal M Valeriani Massimiliano M Vari Maria Stella MS Verrotti Alberto A Vigevano Federico F Vignoli Aglaia A Toonen Ruud R Zara Federico F Helbig Ingo I Striano Pasquale P

Neurology. Genetics 20220531 3

<h4>Background and objectives</h4>Clinical manifestations in <i>STXBP1</i> developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with <i>STXBP1</i>-DEE and dissect the relationship between neurodevelopment and epilepsy.<h4>Methods</h4>Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score syst ...[more]

PMID: 35655584

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Project description:STXBP1-related disorders are among the most common genetic epilepsies and neurodevelopmental disorders. However, the longitudinal epilepsy course and developmental endpoints have not yet been described in detail, which is a critical prerequisite for clinical trial readiness. Here, we assessed 1,281 cumulative patient-years of seizure and developmental histories in 162 individuals with STXBP1-related disorders and established a natural history framework. STXBP1-related disorders are characterized by a dynamic pattern of seizures in the first year of life and high variability in neurodevelopmental trajectories in early childhood. Epilepsy onset differed across seizure types, with 90% cumulative onset for infantile spasms by 6 months and focal-onset seizures by 27 months of life. Epilepsy histories diverged between variant subgroups in the first 2 years of life, when individuals with protein-truncating variants and deletions in STXBP1 (n=39) were more likely to have infantile spasms between 5 and 6 months followed by seizure remission, while individuals with missense variants (n=30) had an increased risk for focal seizures and ongoing seizures after the first year. Developmental outcomes were mapped 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. Quantification of endpoints revealed high variability during the first five years of life, with emerging stratification between clinical subgroups, most prominently between individuals with and without infantile spasms. We found that individuals with neonatal seizures or early infantile seizures followed by seizure offset by 12 months of life had more predictable seizure trajectories in early to late childhood than compared to individuals with more severe seizure presentations, including individuals with refractory epilepsy throughout the first year. Characterization of anti-seizure medication response revealed age-dependent response over time, with phenobarbital, levetiracetam, topiramate, and adrenocorticotropic hormone effective in reducing seizures in the first year of life, while clobazam and the ketogenic diet were effective in long-term seizure management. Virtual clinical trials using seizure frequency as the primary outcome resulted in wide range of trial success probabilities across the age span, with the highest probability in early childhood between 1 year and 3.5 years. In summary, we delineated epilepsy and developmental trajectories in STXBP1-related disorders using standardized measures, providing a foundation to interpret future therapeutic strategies and inform rational trial design.

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