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Erin Alward Boese, Nieraj Jain, Yali Jia, Catie Schlechter, Cary Harding, David Huang, Richard G Weleber, Melanie Gillingham, Mark E Pennesi; Genotype-phenotype correlation in retinopathy associated with mitochondrial trifunctional protein disorders: Long-term follow-up of 21 cases. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2880.
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We assess long-term effects of genotype and metabolic control on retinopathy severity in subjects with mitochondrial trifunctional protein disorders.
This is a retrospective review of all patients evaluated at our institution from 1994 to 2014 with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) or mitochondrial trifunctional protein deficiency (MTPD). All subjects underwent psychophysical testing and electroretinography, and select subjects also underwent multimodal imaging including optical coherence tomography (OCT) angiography. Subjects also participated in a diet optimization program with analysis of serum hydroxyacyl carnitines.
Twenty-one subjects were followed for a median of 5.5 years (range 0.0-20.2). Median age at the initial and final visit were 5.0 (range 0.4-17.7) and 10.5 (range 3.1-24.2) years, respectively. Three subjects (14.3%) had MTPD and 18 (85.7%) had LCHADD. All subjects with LCHADD carried at least one copy of the common mutation (1528G>C) in the HADHA gene, and 9 (50%) were homozygous for this mutation.<br /> <br /> Mean logarithm of the minimum angle of resolution (LogMAR) for LCHADD subjects was 0.20 ±0.25 at baseline and 0.42 ±0.40 at the final visit. Subjects with MTPD had excellent and stable BCVA, with mean final LogMAR 0.0 ±0.0. Despite extensive posterior pole disease, 88% of LCHADD patients had final LogMAR ≤0.30 in the better seeing eye. Subjects with LCHADD, but not MTPD, had a mean decrease in spherical equivalent of 0.40 ±0.37 diopters per year, demonstrating strong inverse correlation with age (ρ =-0.82 in homozygous subjects).<br /> <br /> OCT imaging demonstrated early outer retinal irregularity, with well demarcated regions of severe outer retinal and RPE atrophy at later stages with choriocapillaris loss by OCT angiography. Serial imaging demonstrated formation of outer retinal tubulations at transition zones, and these lesions were identified in all imaged LCHADD eyes.
Long term follow up with multimodal imaging in this large cohort illustrates the worse ocular phenotype in LCHADD as compared to MTPD, with progressive chorioretinal atrophy, prominent outer retinal tubulations, and diffuse choriocapillaris loss. LCHADD subjects also had progressive myopia and declining visual function. Interestingly, most subjects retain reading vision in at least one eye.
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