A Decade in the Making: Newborn Screening for PDE
For families navigating rare inborn errors of metabolism, the newborn screening heel-prick represents a critical safety net: the difference between an early, proactive intervention and months of devastating diagnostic limbo.
The addition of Pyridoxine-Dependent Epilepsy (PDE-ALDH7A1) to the next newborn screening kit marks a transformative milestone for our rare disease community. For an Organic Acidemia Association (OAA) community that knows all too well how metabolic pathway disruptions can derail neurological development, seeing PDE recognized at the screening level validates years of relentless research, physician advocacy, and family perseverance.
However, getting PDE included in the testing kit is only the first phase. Translating this breakthrough into an active, everyday test across all fifty states is where the real work begins.
What Is PDE and Why Does It Belong on the Newborn Screening Panel?
PDE is an inherited metabolic disorder of lysine catabolism caused primarily by mutations in the ALDH7A1 gene (encoding the enzyme antiquitin). When this pathway is disrupted, toxic metabolic intermediates—chiefly alpha-aminoadipic semialdehyde (-AASA) and piperideine-6-carboxylate (P6C)—accumulate. P6C chemically binds and inactivates pyridoxal 5′-phosphate (PLP), the active form of vitamin B6 essential for neurotransmitter synthesis.
Without active B6, infants develop severe, intractable seizures that standard anti-seizure medications fail to control. Left untreated, the condition leads to encephalopathy, severe intellectual disability, or fatal outcomes.
What makes PDE such a classic candidate for universal newborn screening is that it meets every core public health screening criterion:
- Early, effective treatment exists: High-dose pyridoxine (vitamin B6) supplementation, paired with a lysine-restricted diet and arginine supplementation (known as the “triple therapy”), can stop seizures and significantly preserve cognitive development.
- Timing is vital: Starting treatment in the first days or weeks of life—before recurrent status epilepticus or toxic lysine byproduct accumulation cause irreversible brain damage—dramatically alters the child’s neurodevelopmental outcome.
- A viable biomarker: Groundbreaking assay development has made it possible to detect reliable biomarkers directly from standard dried blood spot (DBS) cards using tandem mass spectrometry.
Voices from the Frontlines: The Coughlin Lab and Cure PDE Foundation
This breakthrough represents a collaborative triumph between dedicated bench scientists and tireless family advocates. Celebrating a decade of focused research, the Coughlin Lab shared:
“PDE will be included in the next newborn screening kit! This is an incredible milestone and a major step toward our ultimate goal: giving every newborn the opportunity to be screened for pyridoxine-dependent epilepsy (PDE)… Having PDE included in the newborn screening kit makes widespread screening possible. BUT we are not finished yet!!
The newborn screening kit still needs FDA approval. Once approved, states will be able to use the kit to screen for PDE, but each state will decide whether PDE results are reported as part of its newborn screening program… For the Coughlin Lab, this announcement is especially meaningful. We have been working toward this goal for 10 years… We could not have reached this point without the researchers, clinicians, collaborators, advocates, and, most importantly, the patients and families who have participated in research and supported this work over the years.”
Echoing this sentiment and underscoring what this means for families on the ground, the Cure PDE Foundation stated:
“Newborn screening for PDE has always been a top priority for Cure PDE Foundation and the families we represent. We are so grateful to the Coughlin Lab for all of their hard work to get PDE added to the testing kit. This is such a huge first step in a goal that means everything to PDE families. Newborn Screening for PDE will save families the heartache and fear that so many families in our foundation have experienced, as well as saving infants from seizures and suffering that come along with not being properly diagnosed and treated accurately for this inborn error of metabolism.
There is more work to be done once this testing kit is FDA approved so we hope rare disease advocates will join us in asking their state legislators to include PDE in their state’s newborn screening program. If you have any questions about this process or want to help, please reach out to Leah Trotter at Leah.Trotter@CurePDE.org.”
What This Means for Families
For parents, this progress is monumental. Historically, infants with PDE endured weeks in neonatal intensive care units, cycling through multiple ineffective anti-epileptic drugs while their brains suffered repeated insults. Atypical presentations—such as delayed-onset seizures or transient responses to other medications—frequently caused months of diagnostic delays.
Screening at birth fundamentally reframes PDE from an emergency reactive diagnosis made during status epilepticus to a proactive metabolic management plan initiated before irreversible symptoms take hold.
The Road Ahead: Turning Kits into Screened Babies
A validated kit does not automatically mean a baby born tomorrow will be screened. Newborn screening in the United States is entirely state-governed. Achieving true nationwide screening for PDE requires navigating several key steps:
FDA Approval of the Testing Kit
Before state public health laboratories can run the kit routinely as an in vitro diagnostic tool, the manufacturer must secure clearance or approval through the FDA.
State-by-State Legislative and Advisory Mandates
Every state public health department has its own newborn screening advisory committee. Even with an approved kit available, each state decides which disorders are reported. Some states have statutory mandates requiring them to adopt new conditions within set timeframes, while others require independent legislative appropriations, rule-making hearings, and public comment periods.
Laboratory Validation and Assay Implementation
Public health laboratories must establish, validate, and fund the specific tandem mass spectrometry (MS/MS) or liquid chromatography assays needed to detect PDE biomarkers reliably.
Clinical Care Coordination and Emergency Protocols
Because neonatal seizures in PDE can develop within hours to days of birth, rapid turnaround is essential. State programs must establish rapid clinical follow-up networks with pediatric neurologists and biochemical geneticists so that an infant with a positive screen immediately receives an emergency supply of pyridoxine and a comprehensive metabolic evaluation.
How the OAA Community Can Answer the Call to Action
As both the Coughlin Lab and Cure PDE emphasize, our community’s voice is the most vital element in bridging the gap between an approved kit and a screened child.
We encourage OAA patients, families, and supporters to:
Contact your state legislators and newborn screening advisory boards: Share your diagnostic journey and urge your state to add PDE to its mandated screening panel as soon as the kit achieves FDA approval.
Connect with partner advocacy efforts: Reach out to Leah Trotter at Leah.Trotter@CurePDE.org to coordinate legislative outreach and access advocacy resources tailored to your home state.
Participate in public comment windows: When your state’s newborn screening board meets to evaluate new conditions, submit written or verbal testimony highlighting why early dietary and vitamin intervention saves lives.
By working together across research labs, advocacy foundations, and family networks, we can ensure that every baby born with PDE gets diagnosed and treated from day one.
CurePDE and the Coughlin lab are currently collaborating on a letter that you can share with your legislators to support PDE newborn screening.
The Science Backing the Screen
Wempe MF, Kumar A, Kumar V, Choi KE, Swanson MD, Friederich PS, Coughlin CR 2nd, Van Hove JLK. Identification of a novel biomarker for pyridoxine-dependent epilepsy: implications for newborn screening. J Inherit Metab Dis. 2019;42(4):565-574. doi:10.1002/jimd.12059
Engelke UFH, van Outersterp RE, Merx J, et al. Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy. J Clin Invest. 2021;131(15):e148272. doi:10.1172/JCI148272
Coughlin CR 2nd, Tseng LA, van Karnebeek CDM. A case for newborn screening for pyridoxine-dependent epilepsy. Cold Spring Harb Mol Case Stud. 2022;8(3):a006197. doi:10.1101/mcs.a006197
Pauly K, Woontner M, Abdenur JE, Wempe MF, Coughlin CR 2nd, Van Hove JLK. Feasibility of newborn screening for pyridoxine-dependent epilepsy. Mol Genet Metab. 2025;144(1-2):109002. doi:10.1016/j.ymgme.2024.109002