Epilepsy and overgrowth-intellectual disability syndromes: a patient organization perspective on collaborating to accelerate pathways to treatment

Abstract

Overgrowth-intellectual disability (OGID) syndromes are a collection of rare genetic disorders with overlapping clinical profiles. In addition to the cardinal features of general overgrowth (height and/or head circumference at least two standard deviations above the mean) and some degree of intellectual disability, the OGID syndromes are often associated with neurological anomalies including seizures. In an effort to advance research in directions that will generate meaningful treatments for people with OGID syndromes, a new collaborative partnership called the Overgrowth Syndromes Alliance (OSA) formed in 2023. By taking a phenotype-first approach, OSA aims to unite research and patient communities traditionally siloed by genetic disorder. OSA has galvanized OGID patient organizations around shared interests and developed a research roadmap to identify and address our community's greatest unmet needs. Here, we describe the literature regarding seizures among those with overgrowth syndromes and present the OSA Research Roadmap. This patient-driven guide outlines the milestones essential to reaching the outcome of effective treatments for OGID syndromes and offers resources for reaching those milestones.

Keywords: DNMT3A; Malan syndrome; NFIX; Tatton-Brown Rahman syndrome, Sotos syndrome, epilepsy; overgrowth; seizures.

Figure 1.

Genes underlying overgrowth are enriched for roles in epigenetic regulation and cell signaling. The genes representing select conditions encode either epigenetic or transcriptional regulators (9/13; green) or cell signaling/kinases (4/13; purple). The epigenetic regulators can be further divided into DNA methylation regulators (dark green; TET3 and DNMT3A), histone modifiers (medium green; NSD1, EZH2, EED, SUZ12, SETD2) and chromatin remodelers (CHD8) and transcription factors (NFIX; light green). The cell signaling proteins can be divided into cell surface receptors (GPC3 and PDGFRB; light purple) and mTOR pathway genes (mTOR and PIK3CA; medium purple). Note that EZH2, EED, and SUZ12 physically interact, which is reflected in the high degree of clinical overlap of their respective conditions.

Figure 2.

OSA Research Roadmap. The OSA has developed a comprehensive roadmap for OGID syndromes. This roadmap was created using shared learning from the Malan Syndrome Foundation and TBRS Community. It may also serve as a template for other OGID syndrome patient advocacy organizations. OGID, overgrowth–intellectual disability; OSA, Overgrowth Syndromes Alliance; Food and Drug Administration (FDA).