# Advanced Genetic Study and Pilot Newborn Screening for Disorders of Pyruvate Metabolism

> **NIH NIH U54** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $161,000

## Abstract

Pyruvate dehydrogenase complex deficiencies (PDCD) are a major class of mitochondrial
diseases, limiting oxidation of carbohydrate for energy production, which is especially important
in the brain. PDCD is the second most common entry within the NAMDC Registry among registry
participants with multiple mitochondrial enzyme defects. The best predictor of survival and
cognitive outcome in those affected with PDCD appears to be the age of onset, with neonatal
presentations typically associated with early death, and childhood onset cases associated with
better survival and with normal or mild to severe cognitive disability. The mean and median ages
of diagnosis of PDCD are about 31 and 12 months, respectively. We have sub-classified PDC
deficient subjects into three different groups with important clinical consequences. Use of
ketogenic diets is currently the main therapeutic intervention in a specific subclass of PDCD, but
can be ineffective and/or lethal in subjects from the other subclasses. The proposed "Advanced
Genetic Study and Pilot Newborn Screening for PDC deficiency" is in part a continuation of the
work we have accomplished in our previous "Natural History and Advanced Genetic Study of PDC
deficiencies", where we have a) identified novel and known genes associated with pyruvate
metabolism, b) have integrated natural history and molecular data with the NAMDC Registry and
other databases, c) have sub-classified PDCD subjects into three groups - primary specific-
primary generalized- and secondary-PDCD, and d) noted that patients diagnosed primary-specific
PDCD would be the ones who would benefit most from initiation of a ketogenic diet. Our Aim #1
is to continue identifying novel genetic etiologies for PDCD using established advanced genetic
analysis technologies in conjunction with functional confirmation when needed, which would
enable better understanding of the pathophysiology of this disorder for future controlled clinical
therapeutic intervention trials. Our Aim #2 is to pilot for the first time a newborn screening (NBS)
protocol using biomarkers and specific molecular tests with the goal of diagnosing newborns with
primary-specific PDCD for early intervention with ketogenic diet for better long-term health and
cognitive outcomes. This pilot NBS PDC protocol is an Ohio-wide endeavor that includes two
other NAMDC sites, which together constitute about 20% of all recruits with mitochondrial
disorders in the NAMDC Registry.

## Key facts

- **NIH application ID:** 10023969
- **Project number:** 5U54NS078059-10
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jirair K Bedoyan
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $161,000
- **Award type:** 5
- **Project period:** 2011-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023969

## Citation

> US National Institutes of Health, RePORTER application 10023969, Advanced Genetic Study and Pilot Newborn Screening for Disorders of Pyruvate Metabolism (5U54NS078059-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10023969. Licensed CC0.

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