# The Natural History of LCHAD Retinopathy

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $530,436

## Abstract

Project Summary
 Application of MS/MS to newborn screening (NBS) has facilitated the early diagnosis and treatment of
infants with fatty acid oxidation disorders (FAOD) leading to decreased infant mortality and morbidity.
Mitochondrial Trifunctional Protein Deficiency (TFP) deficiency, including Long-chain 3-Hdyroxyacyl-CoA
Dehydrogenase (LCHAD) deficiency, are two FAOD currently included in US NBS for which prevention of
hypoketotic hypoglycemia, lactic acidosis, and cardiomyopathy is generally achieved with early diagnosis and
institution of contemporary dietary therapy. However, progression of chorioretinopathy with vision loss
associated with LCHAD/TFP deficiencies has been observed in almost all patients despite early diagnosis and
initiation of treatment. Progressive retinopathy in LCHAD/TFP is a unique complication not observed in other
FAOD and the underlying etiology of the retinopathy is not completely understood. The specific focus of this
application is to characterize the progression of chorioretinopathy in a prospective natural history study,
determine clinical and physiologic factors that are associated with retinal changes and vision loss and estimate
the rate of retinal change in a cohort of patients with LCHAD and TFP deficiencies.
 We propose conducting a prospective deep phenotyping study of LCHAD/TFP deficient retinopathy
among 44 patients diagnosed with LCHAD/TFP deficiencies followed over time. The retinal degeneration is
thought to begin with the loss of the retinal pigment epithelium (RPE) and is associated with increased
LCHAD/TFP specific plasma metabolites, hydroxyacylcarnitines, increasing age, number of hospitalizations
and genetic mutations. Using recent advances in neural retinal imaging including autofluoresence, structural
optical coherence tomography (OCT), OCT angiography (OCTA), microperimetry, we will image the layers of
the retina in patients with LCHAD/TFP stratified by age at various stages of progression. Our hypothesis is that
loss of RPE will precede both choriocapillaris dropout and photoreceptor degeneration suggesting the RPE is
the initial cell layer affected in the progression of LCHADD/TFPD retinopathy. We will correlate changes in
retinal structure and measures of visual acuity to environmental factors associated with progression of retinal
degeneration. Our hypothesis is that increased metabolic crisis, higher hydroxyacylcarnitines, and older age
will be associated with RPE loss, visual function decline and decreased quality of life suggesting a toxic
intermediate etiology to the progression of LCHAD-retinopathy. Each subject enrolled in the cohort will be
evaluated on two occasions, approximately 2 years apart to estimate the rate of change over time. The results
will help us understand the etiology of retinopathy and potentially suggest a treatment approach such as retinal
gene therapy to halt retinal degeneration and prevent vision loss.

## Key facts

- **NIH application ID:** 10017307
- **Project number:** 5R01HD095968-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Melanie B Gillingham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $530,436
- **Award type:** 5
- **Project period:** 2019-09-13 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017307

## Citation

> US National Institutes of Health, RePORTER application 10017307, The Natural History of LCHAD Retinopathy (5R01HD095968-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10017307. Licensed CC0.

---

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