# Understanding the Role of NAD Deficiency in a Mendelian Disorder of Tryptophan Metabolism

> **NIH HD F31** · BAYLOR COLLEGE OF MEDICINE · 2026 · $47,314

## Abstract

PROJECT SUMMARY/ABSTRACT
Genetic disruptions of the kynurenine pathway (KP) have been linked to congenital nicotinamide adenine
dinucleotide (NAD) deficiencies in families with a history of birth defects and recurrent miscarriages. Mammals
synthesize NAD from two pathways. The KP synthesizes NAD de novo from dietary tryptophan, whereas the
Preiss-Handler pathway (PHP) bypasses the KP and utilizes dietary niacin. Birth defects associated with
congenital NAD deficiency disorders (CNDD) include vertebral, anal, cardiac, tracheoesophageal, renal, and
limb anomalies. Some individuals with CNDD also have global developmental delays, learning disorders, and
autism. Through the Undiagnosed Diseases Network at Baylor College of Medicine (BCM), we identified a patient
with biallelic variants in kynurenine 3-monooxygenase (KMO). KMO encodes an enzyme that catalyzes a key
step in the KP and has not been previously associated with CNDD. The proband presents with congenital
anomalies, short stature, neurodevelopmental delays, low plasma levels of NAD, and extremely elevated plasma
levels of metabolites upstream of KMO (kynurenine and kynurenate). While indicative of a deficiency in KMO,
the relative contribution of low NAD levels versus elevated upstream metabolites to her phenotypes is unclear.
Moreover, it is not known which phenotypes associated with this disorder may be prevented by supplementing
dietary niacin. I propose to use two mouse models of KMO deficiency and dietary manipulations to better
understand the metabolic mechanisms underlying the phenotypes associated with KMO deficiency. My central
hypothesis is that KMO deficiency is a novel CNDD that increases the risk for congenital anomalies and
neurodevelopmental phenotypes, some of which are preventable with niacin supplementation. Overall,
the findings from these studies will provide insights into strategies for preventing and treating the phenotypes
associated with KMO deficiency and other CNDDs. To understand the 

## Key facts

- **NIH application ID:** 11266118
- **Project number:** 5F31HD115407-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Nathalie Marie Aceves
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** HD
- **Fiscal year:** 2026
- **Award amount:** $47,314
- **Award type:** 5
- **Project period:** 2025-01-06T00:00:00 → 2028-01-05T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11266118

## Citation

> US National Institutes of Health, RePORTER application 11266118, Understanding the Role of NAD Deficiency in a Mendelian Disorder of Tryptophan Metabolism (5F31HD115407-02). Retrieved via AI Analytics 2026-07-09 from https://api.ai-analytics.org/grant/nih/11266118. Licensed CC0.

---

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