# Pyruvate dehydrogenase encephalopathy: mechanisms and therapy

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $354,375

## Abstract

ABSTRACT
This proposal constitutes one of the first mechanistic investigations of pyruvate dehydrogenase (PDH) deficiency
encephalopathy (PDHD), an inborn developmental brain disorder. PDHD leads to impaired brain metabolism
and neurological dysfunction that manifests as intellectual disability and intractable seizures in infants and
children. The elementary biochemical framework has been elucidated primarily in vitro using cell cultures and
homogenates. Normally PDH receives about 80% of the brain’s glucose metabolic flux, converting it into
substrate for the tricarboxylic acid (TCA) cycle. The TCA cycle is responsible for brain energy generation and
also for the synthesis of the neurotransmitters glutamate and GABA, which regulate excitability. The remainder
20% of brain glucose refills natural TCA cycle precursor loss, which is accomplished through a separate process
known as anaplerosis. Yet, anaplerosis can also be secondarily downregulated in PDHD. Nevertheless, despite
these long-established biochemical principles, it is unknown how PDHD causes encephalopathy. In particular,
very little is known about metabolism or excitability within PDHD brain tissue and even less is known in an in
vivo context. This knowledge gap drastically limits therapy, as illustrated by the drug-refractoriness of PDHD
seizures. The objectives of this application are to characterize in vivo abnormal neural excitability and
metabolism in a novel, robust PDHD mouse model and to mitigate them by stimulating both the TCA cycle and
anaplerosis with alternative dietary substrates. Our preliminary results include abnormal neocortical excitability
in PDHD in vivo and amelioration of brain TCA cycle precursor depletion, and thus justify investigating these
mechanisms in greater depth. This leads to a first general hypothesis that metabolic fuel-dependent (rather than
fixed) cortical dysfunction is a central feature of disease pathophysiology. The proposal also includes the
therapeutic consideration that ketone bodies containing an even number of carbons, generated from common
dietary fats or a ketogenic diet, can fuel the TCA cycle and ameliorate seizures in PDHD patients, but cannot
correct anaplerotic deficits. In contrast, our data that exogenous anaplerotic fat metabolites containing an odd
number of carbons can additionally refill brain TCA cycle precursors, lead to a second general hypothesis: That
odd-carbon fat restores neural function in PDHD more effectively via anaplerosis than even-carbon fat. These
two general hypotheses will be tested in three aims: 1) Investigate the electrophysiological bases of cortical
hyperexcitability in PDHD; 2) Test key metabolic mechanisms relevant to synaptic function; 3) Restore brain
metabolism and excitability via anaplerotic odd-carbon fat derivatives. In summary, we expect to help define
PDHD as an excitability disorder and establish the therapeutic value of anaplerotic modulation, thus initiating the
first step of a medical prac...

## Key facts

- **NIH application ID:** 10000180
- **Project number:** 5R01NS102588-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Juan M. Pascual
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,375
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000180

## Citation

> US National Institutes of Health, RePORTER application 10000180, Pyruvate dehydrogenase encephalopathy: mechanisms and therapy (5R01NS102588-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10000180. Licensed CC0.

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