# Newborn screening and treatment monitoring for patients with pyridoxine-dependent epilepsy

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2023 · $194,375

## Abstract

Project Summary:
Pyridoxine-dependent epilepsy (PDE) is a developmental and epileptic encephalopathy that was historically
defined by a positive clinical response to pyridoxine. Despite adequate seizure control, the majority of
patients have developmental delay and intellectual disability. PDE is due to a deficiency of α-aminoadipic
semialdehyde (α-AASA) dehydrogenase, a key enzyme in lysine metabolism that results in the
accumulation of α-AASA and related metabolites. We initially focused on reducing the accumulation of α-
AASA through a lysine-restricted diet and a competitive inhibitor of lysine transport. These novel treatment
strategies improved the overall biochemistry and are associated with normal cognitive development.
Although effective, treatment must be started early in life to prevent irreversible brain disease.
Unfortunately, most patients are diagnosed after treatment is no longer effective. Our central hypothesis is
that the delay in diagnosis and subsequent treatment is the main contributor of intellectual disability
associated with this disease.
The primary focus of this application is development of a newborn screen method for patients with PDE.
Newborn screening provides an opportunity to diagnosis patients before irreversible neurologic damage
occurs dramatically changing the natural history of this disease. Previous attempts at newborn screening
were unsuccessful as α-AASA is unstable at room temperatures and, therefore, not practical for newborn
screening. In our previous work, we identified a novel biomarker (6-oxo-pipecolate) that is stable at room
temperatures and overcomes previous hurdles with newborn screening. We will demonstrate that newborns
with PDE can be diagnosed at birth using current newborn screening techniques (Aim 1). These results will
establish that 6-oxo-pipecoalte is elevated in affected newborns and will provide the basis for future studies
focused on the sensitivity of our newborn screening method.
Although α-AASA is an excellent diagnostic biomarker, the level of α-AASA does not correlate with disease
severity or cognitive outcome. These results are confounded by the unstable nature of α-AASA, which
makes it difficult to compare levels between samples and laboratories. We purpose that 6-oxo-pipecolate is
an ideal biomarker to monitor treatment efficacy. We will evaluate the use of an at-home collection method
for 6-oxo-pipecolate using our existing dried blood spot method. The benefit of at home treatment
monitoring has never been more relevant than during this current pandemic due to the novel coronavirus
COVID-19. We will demonstrate that measuring 6-oxo-pipecolate from dried blood spots collected at home
is a feasible (Aim 2). These results will be critical for futures studies evaluating novel therapeutic
approaches to this this treatable but severe neurologic disease.

## Key facts

- **NIH application ID:** 10640061
- **Project number:** 5R21HD104952-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Curtis R Coughlin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2022-06-08 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10640061

## Citation

> US National Institutes of Health, RePORTER application 10640061, Newborn screening and treatment monitoring for patients with pyridoxine-dependent epilepsy (5R21HD104952-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10640061. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*