STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy

Area of Science:

• Genetics and Neurology
• Neurodevelopmental Disorders
• Epilepsy Syndromes

Background:

• STXBP1 mutations are increasingly recognized as a significant cause of early-onset epilepsy and encephalopathy.
• Understanding the full phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) is crucial for diagnosis and management.
• Previous reports have highlighted various features, but a comprehensive overview is needed.

Purpose of the Study:

• To provide a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E).
• To systematically review newly diagnosed and previously reported patients with STXBP1 mutations.
• To characterize the range of clinical manifestations and genetic variations in STXBP1-E.

Main Methods:

• Recruitment of newly diagnosed STXBP1-E patients through an international clinical and genetic network.
• Systematic literature search to gather data on previously reported STXBP1-E patients.
• Phenotypic analysis of a combined cohort of 147 patients, including 45 novel cases with 33 new STXBP1 mutations.

Main Results:

• 147 patients with STXBP1-E were analyzed, including 45 unreported cases with 33 novel mutations.
• All patients exhibited intellectual disability (ID), predominantly severe to profound (88%).
• Epilepsy affected 95% of patients, with Ohtahara syndrome (21%) and West syndrome (9.5%) noted, but most had non-syndromic early-onset epilepsy (53%). No correlation was found between seizure severity, ID, or mutation type.

Conclusions:

• De novo STXBP1 mutations are a frequent cause of epilepsy and encephalopathy.
• STXBP1-E presents with severe ID and epilepsy, with seizure severity and ID appearing as independent phenotypic dimensions.
• STXBP1-E should be viewed as a complex neurodevelopmental disorder rather than solely an epileptic encephalopathy.