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.
Patients with long-chain-3-hydroxyacyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency develop a unique retinal degeneration that progresses over the lifespan leading to significant vision loss and decreased quality of life. There are currently no treatments for this genetic retinal disorder and the underlying etiology is not fully understood. We propose conducting a detailed prospective natural history study among 44 subjects with LCHAD/TFP to help elucidate retinal pathology, describe the clinical and environmental factors associated with vision loss and estimate the time course and rate of retinal decline across various ages.
