Dysfunctional spectrum associated with clinical phenotype expansion in SCN2A-related disorders

This paper was written by scholars including Anne T. Berg, Christopher H. Thompson, Leah Schust Myers, Erica Anderson, Lindsey Evans, Ariela J. E. Kaiser, Katherine Paltell, Amanda N. Nili, Jean-Marc L. Dekeyser, Tatiana V. Abramova, Gerry Nesbitt, Shawn M. Egan, Carlos G. Vanoye, and Alfred L. George Jr. The paper was published on April 23, 2024, in the journal ‘Brain’. The research was conducted jointly by multiple institutions, including Northwestern University Feinberg School of Medicine, FamiliesSCN2A Foundation, and others.

Academic Background

The SCN2A gene is associated with encoding the voltage-gated sodium channel Nav1.2. SCN2A gene variants can lead to multiple clinical phenotypes, such as epilepsy, autism, and various severe to extreme functional impairments. The expression of these variants shows great heterogeneity. This paper aims to further understand the relationship between these clinical phenotypes and channel functions, providing a more comprehensive understanding through systematic phenotype analysis and functional assessment.

Research Source

This research was mainly conducted with support from the FamiliesSCN2A Foundation and the Channelopathy Associated Epilepsy Research Center Without Walls (CWOW). The study was carried out from April to November 2021, with parents participating through the foundation’s outreach program. Participants came from North America, South America, Europe, Israel, and other regions.

Research Process

Research Subjects and Procedures

The study included 81 patients (36 females, 44%, median age 5.4 years) carrying unique SCN2A gene variants, totaling 69 distinct variants. Through the FamiliesSCN2A Foundation, patients underwent systematic phenotype analysis, and Nav1.2 channel function was systematically evaluated.

Main Procedures:

1. Clinical Phenotype Classification: Based on the age of seizure onset, primary phenotypes were classified as neonatal onset ( month), infantile onset (1-11 months), and late onset (≥12 months), as well as autism without epilepsy (ASD/ID).

2. Functional Performance and Variant Type Assessment:

   • Channel Function Analysis: Using high-throughput automated patch-clamp recording to analyze the impact of different pathogenic variants causing epilepsy on channel function.
   • Variant Functional Scoring and Classification: Categorizing variant functions into gain-of-function (GOF), loss-of-function (LOF), mixed function, and wild-type-like (WT-like) based on different functional parameters.

3. Non-Epilepsy Phenotype Assessment:

   • Motor and Communication Skills: Assessing patients’ motor and communication abilities based on the Gross Motor Function Classification System and Communication Function Classification System.
   • Other Neurological and Medical Comorbidities: Including dependence on food intake, scoliosis, and cortical visual impairment (CVI).

4. Non-Epilepsy Severity Index: Creating a severity index from 0 to 6 based on the combined values of severe motor, communication, and hand use impairments, gastrostomy tube dependence, CVI, and scoliosis.

Data Analysis

Using average linkage and hierarchical cluster analysis with a trimming factor of 5% to explore multivariate relationships among primary phenotypes, variant functions, and phenotype severity.

Main Results

1. Relationship between Phenotype Severity and Primary Phenotype:

   • Non-epilepsy severity was closely related to the age of first seizure (p=0.002). The neonatal onset group had the highest severity, while the autism group had the lowest.
   • Similar severe impairment in communication ability across phenotype groups, but significant differences in motor function and severe CVI impairment between groups.

2. Relationship between Variant Function and Phenotype:

   • The neonatal onset group showed more GOF and mixed function variants.
   • LOF and severe LOF variants were more common in later onset groups and the ASD/ID group.
   • Cluster analysis confirmed several groupings, including infantile onset with moderate LOF, late onset with mixed/WT-like, and neonatal onset with GOF or mixed function.

Research Conclusions

This paper reveals the complex relationship between clinical features caused by SCN2A variants and different Nav1.2 channel functions through systematic phenotype classification and variant functional analysis. It emphasizes the important roles of variant type, age of seizure onset, and non-epilepsy severity in SCN2A-related disorders. These findings have important guiding value for future precision treatments and selection of clinical trial subjects.

Research Highlights

1. Extensive Phenotype Classification and Functional Assessment: First systematic evaluation of SCN2A-related variant functions, providing a comprehensive understanding combined with clinical phenotypes.
2. Strong Association between Clinical and Variant Functions: Clearly established the close relationship between primary phenotypes, variant types, and different clinical phenotypes of patients, providing strong evidence for future personalized treatments.
3. Extensive Participation and Efficient Data Collection: The study recruited through the FamiliesSCN2A Foundation and conducted systematic data collection through an online platform, improving the completeness and authenticity of the data.

This paper expands our understanding of SCN2A-related disorders by in-depth study of the complex relationship between SCN2A variant functions and clinical phenotypes, providing important directional guidance for future precision medicine. This research model demonstrates the importance of collaboration between basic research and parent advocacy organizations, promoting progress in rare disease research.