Johannes Birtel1, Christina von Landenberg2, Martin Gliem3, Carla Gliem4, Jens Reimann4, Wolfram S Kunz5, Philipp Herrmann6, Christian Betz7, Richard Caswell8, Victoria Nesbitt9, Cornelia Kornblum2, Peter Charbel Issa10. 1. Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom; Department of Ophthalmology, University Hospital Bonn, Bonn, Germany; Center for Rare Diseases Bonn (ZSEB), University Hospital Bonn, Bonn, Germany. 2. Center for Rare Diseases Bonn (ZSEB), University Hospital Bonn, Bonn, Germany; Department of Neurology, Section of Neuromuscular Diseases, University Hospital Bonn, Bonn, Germany. 3. Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom. 4. Department of Neurology, Section of Neuromuscular Diseases, University Hospital Bonn, Bonn, Germany. 5. Department of Epileptology, Life & Brain Center, University Hospital Bonn, Bonn, Germany. 6. Department of Ophthalmology, University Hospital Bonn, Bonn, Germany; Center for Rare Diseases Bonn (ZSEB), University Hospital Bonn, Bonn, Germany. 7. Bioscientia Center for Human Genetics, Ingelheim, Germany. 8. Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom; Institute of Biomedical and Clinical Science, University of Exeter School of Medicine, Exeter, United Kingdom. 9. NHS Highly Specialised Service for Rare Mitochondrial Disorders, Nuffield Department of Women's & Reproductive Health, The Churchill Hospital, Oxford, United Kingdom. 10. Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom. Electronic address: study-enquiry@outlook.com.
Abstract
PURPOSE: To report the retinal phenotype and the associated genetic and systemic findings in patients with mitochondrial disease. DESIGN: Retrospective case series. PARTICIPANTS: Twenty-three patients with retinopathy and mitochondrial disease, including chronic progressive external ophthalmoplegia (CPEO), maternally inherited diabetes and deafness (MIDD), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Kearns-Sayre syndrome, neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, and other systemic manifestations. METHODS: Review of case notes, retinal imaging, electrophysiologic assessment, molecular genetic testing including protein modeling, and histologic analysis of muscle biopsy. MAIN OUTCOME MEASURES: Phenotypic characteristics of mitochondrial retinopathy. RESULTS: Genetic testing identified sporadic large-scale mitochondrial DNA deletions and variants in MT-TL1, MT-ATP6, MT-TK, MT-RNR1, or RRM2B. Based on retinal imaging, 3 phenotypes could be differentiated: type 1 with mild, focal pigmentary abnormalities; type 2 characterized by multifocal white-yellowish subretinal deposits and pigment changes limited to the posterior pole; and type 3 with widespread granular pigment alterations. Advanced type 2 and 3 retinopathy presented with chorioretinal atrophy that typically started in the peripapillary and paracentral areas with foveal sparing. Two patients exhibited a different phenotype: 1 revealed an occult retinopathy, and the patient with RRM2B-associated retinopathy showed no foveal sparing, no severe peripapillary involvement, and substantial photoreceptor atrophy before loss of the retinal pigment epithelium. Two patients with type 1 disease showed additional characteristics of mild macular telangiectasia type 2. Patients with type 1 and mild type 2 or 3 disease demonstrated good visual acuity and no symptoms associated with the retinopathy. In contrast, patients with advanced type 2 or 3 disease often reported vision problems in dim light conditions, reduced visual acuity, or both. Short-wavelength autofluorescence usually revealed a distinct pattern, and near-infrared autofluorescence may be severely reduced in type 3 disease. The retinal phenotype was key to suspecting mitochondrial disease in 11 patients, whereas 12 patients were diagnosed before retinal examination. CONCLUSIONS: Different types of mitochondrial retinopathy show characteristic features. Even in absence of visual symptoms, their recognition may facilitate the often challenging and delayed diagnosis of mitochondrial disease, in particular in patients with mild or nebulous multisystem disease.
PURPOSE: To report the retinal phenotype and the associated genetic and systemic findings in patients with mitochondrial disease. DESIGN: Retrospective case series. PARTICIPANTS: Twenty-three patients with retinopathy and mitochondrial disease, including chronic progressive external ophthalmoplegia (CPEO), maternally inherited diabetes and deafness (MIDD), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Kearns-Sayre syndrome, neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, and other systemic manifestations. METHODS: Review of case notes, retinal imaging, electrophysiologic assessment, molecular genetic testing including protein modeling, and histologic analysis of muscle biopsy. MAIN OUTCOME MEASURES: Phenotypic characteristics of mitochondrial retinopathy. RESULTS: Genetic testing identified sporadic large-scale mitochondrial DNA deletions and variants in MT-TL1, MT-ATP6, MT-TK, MT-RNR1, or RRM2B. Based on retinal imaging, 3 phenotypes could be differentiated: type 1 with mild, focal pigmentary abnormalities; type 2 characterized by multifocal white-yellowish subretinal deposits and pigment changes limited to the posterior pole; and type 3 with widespread granular pigment alterations. Advanced type 2 and 3 retinopathy presented with chorioretinal atrophy that typically started in the peripapillary and paracentral areas with foveal sparing. Two patients exhibited a different phenotype: 1 revealed an occult retinopathy, and the patient with RRM2B-associated retinopathy showed no foveal sparing, no severe peripapillary involvement, and substantial photoreceptor atrophy before loss of the retinal pigment epithelium. Two patients with type 1 disease showed additional characteristics of mild macular telangiectasia type 2. Patients with type 1 and mild type 2 or 3 disease demonstrated good visual acuity and no symptoms associated with the retinopathy. In contrast, patients with advanced type 2 or 3 disease often reported vision problems in dim light conditions, reduced visual acuity, or both. Short-wavelength autofluorescence usually revealed a distinct pattern, and near-infrared autofluorescence may be severely reduced in type 3 disease. The retinal phenotype was key to suspecting mitochondrial disease in 11 patients, whereas 12 patients were diagnosed before retinal examination. CONCLUSIONS: Different types of mitochondrial retinopathy show characteristic features. Even in absence of visual symptoms, their recognition may facilitate the often challenging and delayed diagnosis of mitochondrial disease, in particular in patients with mild or nebulous multisystem disease.