# Mechanisms of epilepsy-related death in Leigh syndrome

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2020 · $411,906

## Abstract

Loss-of-function mutations in NDUFS4, the gene that encodes a subunit of the protein complex I in the
mitochondrial electron transport chain, are strongly associated with Leigh Syndrome (LS). LS, or subacute
necrotizing encephalopathy, is a debilitating progressive neurodegenerative disorder. It typically presents with
multi-systemic clinical symptoms which result in disability and ultimately death by 3 years of age.
Mouse models of LS, generated by global or CNS specific Knock Out (KO) of Ndufs4, exhibit several key
clinical features of human LS, including failure to thrive, growth retardation, ataxia, hypotonia, visual problems,
breathing irregularities, and spontaneous seizures and deaths. Our preliminary studies of conditional Ndufs4
KO mice reveal that the epilepsy phenotype can be dissociated from most of the other features of LS, using
genetic approaches. Selective KO of Ndufs4 in GABAergic (not glutamatergic) neurons causes spontaneous
seizures and leads to sudden death in mice. Therefore, work in this proposal will explore the intriguing
possibility that Ndufs4 is a SUDEP gene and GABAergic neuron dysfunction, caused by its KO, is the principal
cause of epilepsy and SUDEP in LS mice. Indeed, these mice present a unique opportunity for functional
studies of SUDEP risks associated with LS-causing Ndufs4 mutation in particular and interneuron dysfunction
in general.
Interestingly, current gene discovery studies have postulated that a SUDEP gene might be best identified as a
mutation or pathogenic variant that causes epilepsy and increases SUDEP risk via central or peripheral
nervous system or end-organ effects on respiratory, cardiac, or other autonomic functions. The forebrain
includes regions known to be involved in seizure generation and the brainstem encompasses control centers
for autonomic functions, commonly affected in SUDEP. In this project, we will examine the role of interneuron
dysfunction in mechanisms SUDEP in Leigh syndrome epilepsy using mouse models. We will: (1) Compare
the contributions of Ndufs4 KO in excitatory (by Vglut2cre) and inhibitory (by Gad2cre) neurons to SUDEP
susceptibility in LS mice; (2) compare the contributions of Ndufs4 KO in forebrain (by Dlxcre12) and brainstem
(by viral cre) GABAergic neurons to SUDEP susceptibility in LS mice; and (3) determine changes in intrinsic
and synaptic functions of forebrain interneurons that contribute to epilepsy and SUDEP pathophysiology in LS
mice. Findings from these studies will provide insights into the mechanisms of sudden death in Leigh
syndrome, the most common form of mitochondrial disorder in children.

## Key facts

- **NIH application ID:** 9948772
- **Project number:** 5R01NS102796-04
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Franck K Kalume
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,906
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948772

## Citation

> US National Institutes of Health, RePORTER application 9948772, Mechanisms of epilepsy-related death in Leigh syndrome (5R01NS102796-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9948772. Licensed CC0.

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