Kctd7 deficiency induces myoclonic seizures associated with Purkinje cell death and microvascular defects

Abstract

Mutations in the potassium channel tetramerization domain-containing 7 (KCTD7) gene are associated with a severe neurodegenerative phenotype characterized by childhood onset of progressive and intractable myoclonic seizures accompanied by developmental regression. Kctd7 (EPM3) is a member of a large family of progressive myoclonic epilepsy (EPM) syndromes displaying a broad spectrum of clinical severity. Animal models of Kctd7-related disease are lacking, and little is known regarding how Kctd7 protein defects lead to epilepsy and cognitive dysfunction. We characterized brain Kctd7 expression patterns during development and show it is selectively enriched in specific regions as the brain matures. We further demonstrate that Kctd7-deficient mice develop seizures and locomotor defects with features similar to those observed in human KCTD7-associated disease. We also show that Kctd7 is required for Purkinje cell survival in the cerebellum and that selective degeneration of these neurons is accompanied by defects in cerebellar brain microvascular organization and patterning. Together, these results define a new model for Kctd7- associated epilepsy and identify Kctd7 as a modulator of neuron survival and excitability linked to microvascular alterations in vulnerable regions.

The involvement of Purkinje cells in progressive myoclonic epilepsy: Focus on neuronal ceroid lipofuscinosis

“…Moreover, a progressive loss of PCs was observed in human patients with two novel KCTD7 mutations and was consistent with the presence of myoclonic or generalized tonic-clonic seizures and abnormal EEGs ( Dai et al, 2019 ). Similarly, myoclonic seizures and locomotor deficits correlated with loss of PCs were shown in a mouse model with a Kctd7 deficiency ( Liang et al, 2022 ).…”

Chiari 1 Malformation and Epilepsy in Children: A Missing Relationship

“…However, although it cannot be excluded, a shared genetic and embryologic maldevelopment pattern between these malformations and CM1 is not demonstrated yet [ 30 ]. KCTD7 deficiency is an example of a shared genetic pathway involving the brain (epilepsy) and cerebellum (degeneration of Purkinje cells) [ 31 ] and could be used as a possible model for research on this topic. To date, a syndrome with a “pure” association between CM1 and epilepsy has not been identified in spite of the recent description of new syndromes, such as the PTEN hamartoma tumor or the SETD2 neurodevelopmental one, which include CM1 and epilepsy [ 32 , 33 ].…”

KCTD7‐related progressive myoclonic epilepsy: Report of 42 cases and review of literature

“…Forty-one records were retrieved and assessed for eligibility. Twenty-three studies were included, [14][15][16][17][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] and 18 studies were excluded 13,[40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56] for the following reasons: variables of interest not reported, 13,[41][42][43][44][47][48][49][50][51]53,…”

“…Forty‐one records were retrieved and assessed for eligibility. Twenty‐three studies were included, 14–17,22–39 and 18 studies were excluded 13,40–56 for the following reasons: variables of interest not reported, 13,41–44,47–51,53,55 duplicate patient population, 40,45,46,52,56 and review article 54 …”