Characterization of Chorioretinopathy Associated with Mitochondrial Trifunctional Protein Disorders

Abstract

Objective To assess long-term effects of genotype on chorioretinopathy severity in subjects with mitochondrial trifunctional protein (MTP) disorders. Design Retrospective case series. Participants Consecutive patients with MTP disorders evaluated at a single center from 1994 to 2015, including 18 subjects with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and 3 subjects with trifunctional protein deficiency (TFPD). Methods Local records from all visits were reviewed. Every subject underwent complete ophthalmic examination and was evaluated by a metabolic physician and dietitian. Nine subjects underwent ancillary fundoscopic imaging including optical coherence tomography (OCT) and OCT angiography. Main Outcome Measures The primary outcome measure was best-corrected visual acuity (logMAR) at the final visit. Secondary outcome measures included spherical equivalent refraction, electroretinogram (ERG) b-wave amplitudes, and qualitative imaging findings. Results Subjects were followed for a median of 5.6 years (range 0.3–20.2). The median age of LCHADD subjects at initial and final visits was 2.3 and 11.9 years, while the median age for TFPD subjects at initial and final visits was 4.7 and 15.5 years. Four long-term survivors over the age of 16 years were included (three subjects with LCHADD and one subject with TFPD). LCHADD subjects demonstrated a steady decline in visual acuity from an average logMAR of 0.23 (Snellen equivalent 20/34) at baseline to 0.42 (Snellen equivalent 20/53) at the final visit, whereas TFPD patients maintained excellent acuity throughout follow up. Subjects with LCHADD, but not TFPD, showed an increasing myopia with a mean decrease in spherical equivalent refraction of 0.24 diopters per year. Multimodal imaging demonstrated progressive atrophy of the outer retina in LCHADD, often preceded by the formation of outer retinal tubulations and choriocapillaris dropout. ERG findings support the more severe clinical profile of LCHADD subjects compared with TFPD; the function of both rods and cones are diffusely attenuated in LCHADD but within normal limits for TFPD subjects. Conclusions Despite improved survival with early diagnosis, medical management, and dietary treatment, subjects with the LCHADD subtype of MTP disorder continue to develop visually disabling chorioretinopathy. Multimodal imaging is most consistent with choriocapillaris loss exceeding photoreceptor loss.

Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle

“…Patients with isolated LCHAD deficiency or generalized MTP deficiency share most of the clinical signs and symptoms with other lcFAODs, but are the only lcFAOD in which patients can develop peripheral neuropathy and pigmentary retinopathy [ 23 – 25 , 62 , 126 – 128 ]. Even though peripheral neuropathy and pigmentary retinopathy are reported in both LCHAD and MTP deficiency, retinopathy seems to be more prevalent in isolated LCHAD deficiency and peripheral neuropathy is more often seen in MTP deficiency [ 127 – 130 ]. There is a broad clinical spectrum, but the proportion of patients with a severe clinical presentation and who are refractory to treatment - despite early detection by NBS - is larger than seen in VLCAD deficiency [ 62 , 131 ].…”

Cryo-EM structure of human mitochondrial trifunctional protein

“…Most of these mutations occur at low frequencies. E510Q in TFPα is by far the most common disease mutant, causing long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and AFLP (5,6,(20)(21)(22)(23). Glu510 is part of the His-Glu catalytic dyad in the active site of HACD (24); and substituting this critical residue by a Gln would abolish HACD activity and jam the β-oxidation cycle at the third step.…”

Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

“…Ocular damage and poor vision is a unique defect observed in patients with LCHAD deficiency that is not common to other inborn errors of fatty acid oxidation defects. Recent studies have shown that LCHAD-deficient individuals develop retinal dysfunction and chorioretinopathy leading to subnormal vision function [ 48 , 102 , 104 , 105 , 106 ]. The ocular damage is typically accompanied by retinal pigmentation, peripheral neuropathy and cognitive deficiency [ 48 , 103 ].…”