Posterior Segment Involvement in Infantile Nephropathic Cystinosis – A Review

Abstract

Cystinosis is a rare lysosomal storage disease with a prevalence of 1 : 100 000 – 1 : 200 000 cases. It is caused by biallelic mutations in the CTNS gene, which encodes cystinosin, that transport cystine out of the lysosomes. Due to its dysfunction, cystine crystals accumulate in the lysosomes and ultimately cause apoptosis of the cell. Since cystinosin is ubiquitously present in the body, cystine crystals are deposited in every body structure and lead to the dysfunction of various organ systems in the course of time. Cystine crystals deposited in the cornea are a clinical hallmark of the disease, while there is less awareness of concomitant posterior segment alterations. Symmetrical pigment epithelial mottling and patches of depigmentation frequently start in the periphery and progress towards the posterior pole and can be encountered upon fundus biomicroscopy. Spectral-domain optical coherence tomography (SD-OCT) is an elegant tool for visualizing chorioretinal cystine crystals at the posterior pole. An SD-OCT-based clinical grading of the severity of the chorioretinal manifestation can potentially be applied as a biomarker for systemic disease status and for monitoring oral therapy adherence in the future. Along with previous histological examinations, it may also give information about the location of cystine crystals in the choroid and retina. This review aims to increase the awareness of vision-threatening retinal and choroidal changes in cystinosis and the concomitant findings in SD-OCT.

Zusammenfassung

Die Cystinose ist eine seltene, autosomal-rezessiv vererbte lysosomale Speicherkrankheit der Aminosäure Cystin mit einer geschätzten Prävalenz von 1 : 100 000 bis 1 : 200 000. Ursächlich sind Mutationen im CTNS-Gen, die für den lysosomalen Aminosäuretransporter Cystinosin codieren. Die Fehlfunktion des Cystinosins führt zu einer Akkumulation von Cystin im Lysosom und letztlich zur Apoptose der Zelle Das intrazelluläre Cystinosin ist ubiquitär im Körper vorhanden, sodass sich Cystinkristalle in jedem Gewebe ablagern und zu einer Dysfunktion verschiedener Organsysteme führen. Korneale Cystinkristallablagerungen sind pathognomonisch für die Erkrankung, während begleitende Veränderungen am hinteren Pol bislang weniger Beachtung fanden. Fundoskopisch sind häufig symmetrische retinale Pigmentepithelauflockerungen und depigmentierte Areale zu erkennen, die in der Peripherie beginnen und zum hinteren Pol fortschreiten. Die optische Kohärenztomografie (SD-OCT) eignet sich sehr gut zur Visualisierung chorioretinaler Cystinkristallablagerungen. Eine SD-OCT-basierte klinische Einstufung des Schweregrads der chorioretinalen Manifestation kann in Zukunft möglicherweise als Biomarker für den systemischen Krankheitsstatus und für die Überwachung der oralen Therapieadhärenz eingesetzt werden. In Zusammenschau mit früheren histologischen Untersuchungen können OCT-morphologische Aufnahmen Aufschluss über die genaue Lokalisation der Cystinkristalle in der Aderhaut und Netzhaut geben. Diese Übersichtsarbeit soll das Bewusstsein für visusbedrohende Netzhaut-und Aderhautveränderungen in der infantilen nephropathischen Cystinose und die begleitenden Befunde im SD-OCT schärfen.

Key words

choroid - genetics - retina

Schlüsselwörter

Retina - Genetik - Chorioidea

Publikationsverlauf

Eingereicht: 15. September 2022

Angenommen: 03. Februar 2023

Artikel online veröffentlicht:
28. März 2023

• References

• 1 Wilmer MJ, Emma F, Levtchenko EN. The pathogenesis of cystinosis: mechanisms beyond cystine accumulation. Am J Physiol Renal Physiol 2010; 299: F905-F916
• 2 Labbe A, Niaudet P, Loirat C. et al. In vivo confocal microscopy and anterior segment optical coherence tomography analysis of the cornea in nephropathic cystinosis. Ophthalmology 2009; 116: 870-876
• 3 Keidel L, Elhardt C, Hohenfellner K. et al. Establishing an objective biomarker for corneal cystinosis using a threshold-based Spectral domain optical coherence tomography imaging algorithm. Acta Ophthalmol 2021; 99: e189-e195
• 4 Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004; 6: 463-477
• 5 Wilmer MJ, Schoeber JP, van den Heuvel LP. et al. Cystinosis: practical tools for diagnosis and treatment. Pediatr Nephrol 2011; 26: 205-215
• 6 Tsilou E, Zhou M, Gahl W. et al. Ophthalmic manifestations and histopathology of infantile nephropathic cystinosis: report of a case and review of the literature. Surv Ophthalmol 2007; 52: 97-105
• 7 David D, Princiero Berlingerio S, Elmonem MA. et al. Molecular Basis of Cystinosis: Geographic Distribution, Functional Consequences of Mutations in the CTNS Gene, and Potential for Repair. Nephron 2019; 141: 133-146
• 8 Tsilou ET, Rubin BI, Reed G. et al. Nephropathic cystinosis: posterior segment manifestations and effects of cysteamine therapy. Ophthalmology 2006; 113: 1002-1009
• 9 Kalatzis V, Antignac C. New aspects of the pathogenesis of cystinosis. Pediatr Nephrol 2003; 18: 207-215
• 10 Jamalpoor A, Othman A, Levtchenko EN. et al. Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis. Trends Mol Med 2021; 27: 673-686
• 11 Schneider JA, Verroust FM, Kroll WA. et al. Prenatal diagnosis of cystinosis. N Engl J Med 1974; 290: 878-882
• 12 Biswas S, Sornalingam K. The Ocular Status of Cystinosis Patients Receiving a Hospital Pharmacy-Made Preparation of Cysteamine Eye Drops: A Case Series. Ophthalmol Ther 2019; 8: 125-136
• 13 Cantani A, Giardini O, Ciarnella Cantani A. Nephropathic cystinosis: ineffectiveness of cysteamine therapy for ocular changes. Am J Ophthalmol 1983; 95: 713-714
• 14 Keidel L, Hohenfellner K, Schworm B. et al. Spectral domain optical coherence tomography-based retinochoroidal cystine crystal score: a window into infantile nephropathic cystinosis. Br J Ophthalmol 2023; 107: 234-241
• 15 Dureau P, Broyer M, Dufier JL. Evolution of ocular manifestations in nephropathic cystinosis: a long-term study of a population treated with cysteamine. J Pediatr Ophthalmol Strabismus 2003; 40: 142-146
• 16 Wong VG, Lietman PS, Seegmiller JE. Alterations of pigment epithelium in cystinosis. Arch Ophthalmol 1967; 77: 361-369
• 17 Richler M, Milot J, Quigley M. et al. Ocular manifestations of nephropathic cystinosis. The French-Canadian experience in a genetically homogeneous population. Arch Ophthalmol 1991; 109: 359-362
• 18 Schneider JA, Wong V, Seegmiller JE. The early diagnosis of cystinosis. J Pediatr 1969; 74: 114-116
• 19 Bishop R. Ocular Complications of Infantile Nephropathic Cystinosis. J Pediatr 2017; 183 S: S19-S21
• 20 Dufier JL, Dhermy P, Gubler MC. et al. Ocular changes in long-term evolution of infantile cystinosis. Ophthalmic Paediatr Genet 1987; 8: 131-137
• 21 Kalatzis V, Serratrice N, Hippert C. et al. The ocular anomalies in a cystinosis animal model mimic disease pathogenesis. Pediatr Res 2007; 62: 156-162
• 22 Richard G, Kroll P. [Retinal changes in cystinosis]. Ophthalmologica 1983; 186: 211-218
• 23 Tsilou E, Csaky K, Rubin BI. et al. Retinal visualization in an eye with corneal crystals using indocyanine green videoangiography. Am J Ophthalmol 2002; 134: 123-125
• 24 Gahl WA, Thoene JG, Schneider JA. et al. NIH conference. Cystinosis: progress in a prototypic disease. Ann Intern Med 1988; 109: 557-569
• 25 Biswas S, Gaviria M, Malheiro L. et al. Latest Clinical Approaches in the Ocular Management of Cystinosis: A Review of Current Practice and Opinion from the Ophthalmology Cystinosis Forum. Ophthalmol Ther 2018; 7: 307-322
• 26 Gahl WA, Kaiser-Kupfer MI. Complications of nephropathic cystinosis after renal failure. Pediatr Nephrol 1987; 1: 260-268
• 27 Nesterova G, Gahl WA. Cystinosis: the evolution of a treatable disease. Pediatr Nephrol 2013; 28: 51-59
• 28 Young B, Eggenberger E, Kaufman D. Current electrophysiology in ophthalmology: a review. Curr Opin Ophthalmol 2012; 23: 497-505
• 29 Vincent A, Robson AG, Holder GE. Pathognomonic (diagnostic) ERGs. A review and update. Retina 2013; 33: 5-12
• 30 Kozak I, Arevalo JF, Shoughy SS. Intraretinal Crystals in Nephopathic Cystinosis and Fanconi Syndrome. JAMA Ophthalmol 2017; 135: e165169
• 31 Nguyen-Ba-Charvet KT, Chedotal A. Development of retinal layers. C R Biol 2014; 337: 153-159
• 32 Gupta MP, Herzlich AA, Sauer T. et al. Retinal Anatomy and Pathology. Dev Ophthalmol 2016; 55: 7-17
• 33 Iwata F, Kuehl EM, Reed GF. et al. A randomized clinical trial of topical cysteamine disulfide (cystamine) versus free thiol (cysteamine) in the treatment of corneal cystine crystals in cystinosis. Mol Genet Metab 1998; 64: 237-242
• 34 Campbell JP, Zhang M, Hwang TS. et al. Detailed Vascular Anatomy of the Human Retina by Projection-Resolved Optical Coherence Tomography Angiography. Sci Rep 2017; 7: 42201
• 35 Vogel DG, Malekzadeh MH, Cornford ME. et al. Central nervous system involvement in nephropathic cystinosis. J Neuropathol Exp Neurol 1990; 49: 591-599
• 36 Thomas WE. Brain macrophages: on the role of pericytes and perivascular cells. Brain Res Brain Res Rev 1999; 31: 42-57
• 37 Farrell CR, Stewart PA, Farrell CL. et al. Pericytes in human cerebral microvasculature. Anat Rec 1987; 218: 466-469
• 38 Gaide Chevronnay HP, Janssens V, Van Der Smissen P. et al. Time course of pathogenic and adaptation mechanisms in cystinotic mouse kidneys. J Am Soc Nephrol 2014; 25: 1256-1269
• 39 Sinha D, Valapala M, Shang P. et al. Lysosomes: Regulators of autophagy in the retinal pigmented epithelium. Exp Eye Res 2016; 144: 46-53
• 40 Dufier JL, Orssaud D, Dhermy P. et al. Ocular changes in some progressive hereditary nephropathies. Pediatr Nephrol 1987; 1: 525-530
• 41 Forrester JV, Xu H, Kuffova L. et al. Dendritic cell physiology and function in the eye. Immunol Rev 2010; 234: 282-304
• 42 Anikster Y, Shotelersuk V, Gahl WA. CTNS mutations in patients with cystinosis. Hum Mutat 1999; 14: 454-458 2-H
• 43 Martin-Begue N, Alarcon S, Wolley-Dod C. et al. Intracranial Hypertension in Cystinosis Is a Challenge: Experience in a Childrenʼs Hospital. JIMD Rep 2017; 35: 17-22
• 44 Parnes A, Wassner SJ, Weinstein JM. A case of intracranial hypertension and papilledema associated with nephropathic cystinosis and ocular involvement. Binocul Vis Strabismus Q 2008; 23: 37-40
• 45 Matthews YY, Dean F, Lim MJ. et al. Pseudotumor cerebri syndrome in childhood: incidence, clinical profile and risk factors in a national prospective population-based cohort study. Arch Dis Child 2017; 102: 715-721
• 46 Dogulu CF, Tsilou E, Rubin B. et al. Idiopathic intracranial hypertension in cystinosis. J Pediatr 2004; 145: 673-678
• 47 Blasco Morente G, Tercedor Sánchez J, Garrido Colmenero C. et al. Pseudotumor cerebri associated with cyclosporine use in severe atopic dermatitis. Pediatr Dermatol 2015; 32: 237-239
• 48 Cherqui S, Courtoy PJ. The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives. Nat Rev Nephrol 2017; 13: 115-131
• 49 Foreman JW. Fanconi Syndrome. Pediatr Clin North Am 2019; 66: 159-167
• 50 Andrzejewska Z, Nevo N, Thomas L. et al. Cystinosin is a Component of the Vacuolar H+-ATPase-Ragulator-Rag Complex Controlling Mammalian Target of Rapamycin Complex 1 Signaling. J Am Soc Nephrol 2016; 27: 1678-1688
• 51 Sansanwal P, Yen B, Gahl WA. et al. Mitochondrial autophagy promotes cellular injury in nephropathic cystinosis. J Am Soc Nephrol 2010; 21: 272-283