Observations regarding retinopathy in mitochondrial trifunctional protein deficiencies

Abstract

Although the retina is thought to primarily rely on glucose for fuel, inherited deficiency of one or more activities of mitochondrial trifunctional protein results in a pigmentary retinopathy leading to vision loss. Many other enzymatic deficiencies in fatty acid oxidation pathways have been described, none of which results in retinal complications. The etiology of retinopathy among patients with defects in trifunctional protein is unknown. Trifunctional protein is a heteroctomer; two genes encode the alpha and beta subunits of TFP respectively, HADHA and HADHB. A common mutation in HADHA, c.1528G>C, leads to a single amino acid substitution, p. Glu474Gln, and impairs primarily long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity leading to LCHAD deficiency (LCHADD). Other mutations in HADHA or HADHB often lead to significant reduction in all three enzymatic activities and result in trifunctional protein deficiency (TFPD). Despite many similarities in clinical presentation and phenotype, there is growing evidence that they can result in different chronic complications. This review will outline the clinical similarities and differences between LCHADD and TFPD, describe the course of the associated retinopathy, propose a genotype/phenotype correlation with the severity of retinopathy, and discuss the current theories about the etiology of the retinopathy.

Fig. 1

a. Pathway of long-chain fatty acid oxidation with blocked activities of TFP and blocked dehydrogenase step and the respective metabolite build up illustrated. b. A cartoon illustration of TFP with subunits and activities labeled.

Fig. 2

a) Normal retinal photograph; b) patient with stage 2 chorioretinopathy of LCHADD, c) patient with stage 4 chorioretinopathy of LCHADD; d) same eye as pictured in panel c illustrating peripheral progression of stage 4 chorioretinopathy.

Fig. 3

ERG waveforms of two age and test condition matched subjects compared to a normal control 30 Hz Flicker and photopic single flash = cone-driven response; scotopic Ops, scotopic single flash = rod-driven response. Patient 4 has lower amplitude and increased implicit time representing rod/cone dysfunction compared to patient 5 and the normal control.