ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes

Abstract

BackgroundTheZFHX3gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship betweenZFHX3variants and epilepsy.MethodsWhole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. ADrosophila Zfh2knockdown model was used to validate the association betweenZFHX3and epilepsy.ResultsCompound heterozygousZFHX3variants were identified in eight unrelated cases. The burden ofZFHX3variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. InZfh2knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. TheZfh2knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated thatZFHX3orthologous were highly expressed in the embryonic stage and decreased dramatically after birth.ConclusionZFHX3is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.

ZFHX3 plays a role in pain and cautious-like behaviours in mice

“…The role of ZFHX3 has been well characterised in circadian rhythms (Balzani et al, 2016; Hughes et al, 2021; Parsons et al, 2015; Wilcox et al, 2017, 2021), as well as metabolism (Nolan et al, 2023; Park, 2022) as ZFHX3 is present in the suprachiasmatic nucleus and the hypothalamus respectively. ZFHX3 also play a role in neurodevelopment (Pérez Baca et al, 2024), and causes spinocerebellar ataxia (Figueroa et al, 2024; Wallenius et al, 2024) and epilepsy (He et al, 2024). This shows that ZFHX3 is involved in various neurophysiology and neuropathology aspects.…”