Observations regarding retinopathy in mitochondrial trifunctional protein deficiencies

• Published in: Molecular genetics and metabolism 2012-05, Vol.106 (1), p.18-24
• Main Authors: Fletcher, Autumn L., Pennesi, Mark E., Harding, Cary O., Weleber, Richard G., Gillingham, Melanie B.
• Format: Article
• Language: English
• Subjects: 3-Hydroxyacyl-CoA dehydrogenase; Acyl-CoA Dehydrogenase, Long-Chain - deficiency; Acyl-CoA Dehydrogenase, Long-Chain - genetics; Acyl-CoA Dehydrogenase, Long-Chain - metabolism; Amino acid substitution; Enzymatic activity; Etiology; Fatty acid oxidation; Fatty acids; Fuels; Genotypes; Glucose; Humans; Hydroxyacylcarnitines; Inborn errors of metabolism; Lipid Metabolism, Inborn Errors - genetics; Lipid Metabolism, Inborn Errors - metabolism; Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; Mitochondria; Mitochondria - enzymology; Mitochondria - pathology; Mitochondrial Trifunctional Protein; Mitochondrial trifunctional protein deficiency; Mitochondrial Trifunctional Protein, alpha Subunit; Mitochondrial Trifunctional Protein, beta Subunit; Multienzyme Complexes - deficiency; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Mutation; Oxidation; Phenotype; Protein deficiency; Retina; Retina - enzymology; Retina - pathology; Retinal Diseases - genetics; Retinal Diseases - metabolism; Retinopathy; Reviews; Vision
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2012.02.015

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. ► Trifunctional protein (TFP) deficiencies, including LCHADD result in retinopathy. ► No other fatty acid oxidation deficiency results in a retinal phenotype. ► This review discusses current theories about etiology of LCHADD retinopathy.