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Drug-Resistant Epilepsy in Tuberous Sclerosis Complex Is Associated With TSC2 Genotype: More Findings From the Preventing Epilepsy Using Vigatrin (PREVeNT) Trial.
Farach, Laura S; Richard, Melissa A; Wulsin, Aynara C; Bebin, Elizabeth M; Krueger, Darcy A; Sahin, Mustafa; Porter, Brenda E; McPherson, Tarrant O; Peters, Jurriaan M; O'Kelley, Sarah; Taub, Katherine S; Rajaraman, Rajsekar; Randle, Stephanie C; McClintock, William M; Koenig, Mary Kay; Frost, Michael D; Werner, Klaus; Nolan, Danielle A; Wong, Michael; Cutter, Gary; Northrup, Hope; Au, Kit Sing.
Afiliación
  • Farach LS; Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children's Memorial Hermann Hospital, Houston, Texas. Electronic address: Laura.S.Farach@uth.tmc.edu.
  • Richard MA; Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
  • Wulsin AC; Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
  • Bebin EM; Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama.
  • Krueger DA; Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
  • Sahin M; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, Massachusetts; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
  • Porter BE; Department of Neurology, Stanford University, Stanford, California.
  • McPherson TO; Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia.
  • Peters JM; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, Massachusetts; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
  • O'Kelley S; Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama.
  • Taub KS; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
  • Rajaraman R; Department of Pediatrics and Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California.
  • Randle SC; Division Pediatric Neurology and Epilepsy, Department of Neurology, Seattle Children's Hospital, Seattle, Washington.
  • McClintock WM; Division of Neurology, Department of Pediatrics, Children's National Medical Center, Washington, District of Columbia.
  • Koenig MK; Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children's Memorial Hermann Hospital, Houston, Texas.
  • Frost MD; Minnesota Epilepsy Group, P.A., Roseville, Minnesota.
  • Werner K; Department of Pediatrics, Duke University, Durham, North Carolina.
  • Nolan DA; Beaumont Florence and Richard McBrien Pediatric Neuroscience Center, Beaumont Hospital, Royal Oak, Michigan.
  • Wong M; Department of Neurology, Washington University in Saint Louis, Saint Louis, Missouri.
  • Cutter G; Department of Biostatistics, University of Alabama at Birmingham, Alabama.
  • Northrup H; Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children's Memorial Hermann Hospital, Houston, Texas.
  • Au KS; Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children's Memorial Hermann Hospital, Houston, Texas.
Pediatr Neurol ; 159: 62-71, 2024 Oct.
Article en En | MEDLINE | ID: mdl-39142021
ABSTRACT

BACKGROUND:

Children with tuberous sclerosis complex (TSC) are at high risk for drug-resistant epilepsy (DRE). The ability to stratify those at highest risk for DRE is important for counseling and prompt, aggressive management, necessary to optimize neurocognitive outcomes. Using the extensively phenotyped PREVeNT cohort, we aimed to characterize whether the TSC genotype was associated with DRE.

METHODS:

The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to first abnormal electroencephalography, and time to epilepsy onset were compared using Fisher exact test and regression models.

RESULTS:

Presence of a TSC2 pathogenic variant was significantly associated with DRE, compared with TSC1 and participants with no pathogenic mutation identified. In fact, all participants with DRE had a TSC2 pathogenic variant. Furthermore, TSC2 variants expected to result in no protein product were associated with higher risk for DRE. Finally, TSC1 pathogenic variants were associated with later-onset epilepsy, on average 21.2 months later than those with other genotypes.

CONCLUSIONS:

Using a comprehensively phenotyped cohort followed from infancy, this study is the first to delineate genotype-phenotype correlations for epilepsy severity and onset in children with TSC. Patients with TSC2 pathogenic variants, especially TSC2 pathogenic variants predicted to result in lack of TSC2 protein, are at highest risk for DRE, and are likely to have earlier epilepsy onset than those with TSC1. Clinically, these insights can inform counseling, surveillance, and management.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esclerosis Tuberosa / Epilepsia Refractaria / Proteína 2 del Complejo de la Esclerosis Tuberosa / Genotipo Límite: Female / Humans / Infant / Male Idioma: En Revista: Pediatr Neurol Asunto de la revista: NEUROLOGIA / PEDIATRIA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esclerosis Tuberosa / Epilepsia Refractaria / Proteína 2 del Complejo de la Esclerosis Tuberosa / Genotipo Límite: Female / Humans / Infant / Male Idioma: En Revista: Pediatr Neurol Asunto de la revista: NEUROLOGIA / PEDIATRIA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos