Corneal Manifestation in Patients with Infantile Nephropathic Cystinosis

Abstract

Nephropathic cystinosis is a rare autosomal recessive disease caused by mutations in the CTNS gene. This causes dysfunction of cystinosin, a protein that transports cystine out of lysosomes, causing cystine crystals to accumulate in cells in most organ systems. While renal complications predominate in the early forms of cystinosis, corneal crystal accumulation will inevitably manifest in all patients. The main symptoms are photophobia along with glare sensitivity and blepharospasm. In addition, corneal crystal accumulation can cause other complications, such as recurrent corneal erosions, punctate or filamentary keratopathy, and chronic dry eye. Eventually, peripheral corneal neovascularization and limbal stem cell deficiency may develop. Ophthalmologists play a key role in the early diagnosis of patients with cystinosis. This review aims to not only raise awareness of secondary complications of corneal crystal accumulation, but also to highlight current treatment options and challenges that ophthalmologists and pediatricians might face.

Zusammenfassung

Die nephropathische Cystinose ist eine seltene autosomal-rezessive Krankheit, bei der Mutationen im CTNS-Gen eine Funktionsstörung des Proteins Cystinosin verursachen. Als Folge kann Cystin nicht mehr aus den Lysosomen transportiert werden und es kommt zu einer Ansammlung von Cystinkristallen in den Zellen fast aller Organsysteme. Hauptsymptome sind Photophobie, Blendempfindlichkeit und Blepharospasmus. Die Ansammlung von Cystinkristallen in der Hornhaut kann überdies weitere Komplikationen wie z. B. rezidivierende Hornhauterosionen, eine filiforme Keratopathie oder ein chronisch trockenes Auge verursachen. Langfristig können periphere Hornhautneovaskularisationen und eine Limbusstammzellinsuffizienz die Folge sein. Augenärzte spielen eine Schlüsselrolle bei der Frühdiagnose von Patienten mit nephropatischer Cystinose. Diese Übersichtsarbeit soll nicht nur einen Überblick über die sekundären Komplikationen einer zunehmenden Ansammlung von Cystinkristallen in der Hornhaut geben, sondern auch die aktuellen Behandlungsmöglichkeiten und Herausforderungen aufzeigen, mit denen sich Augenärzte und Kinderärzte konfrontiert sehen könnten.

Key words

cornea - corneal cystine crystals - genetics

Schlüsselwörter

Kornea - Kinderophthamologie - Genetik

Publication History

Received: 05 October 2022

Accepted: 24 January 2023

Accepted Manuscript online:
25 January 2023

Article published online:
28 March 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 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
• 3 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
• 4 Anikster Y, Lucero C, Guo J. et al. Ocular nonnephropathic cystinosis: clinical, biochemical, and molecular correlations. Pediatr Res 2000; 47: 17-23
• 5 Ariceta G, Giordano V, Santos F. Effects of long-term cysteamine treatment in patients with cystinosis. Pediatr Nephrol 2019; 34: 571-578
• 6 Park M, Helip-Wooley A, Thoene J. Lysosomal cystine storage augments apoptosis in cultured human fibroblasts and renal tubular epithelial cells. J Am Soc Nephrol 2002; 13: 2878-2887
• 7 Rega LR, Polishchuk E, Montefusco S. et al. Activation of the transcription factor EB rescues lysosomal abnormalities in cystinotic kidney cells. Kidney Int 2016; 89: 862-873
• 8 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
• 9 Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med 2002; 347: 111-121
• 10 Cherqui S, Courtoy PJ. The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives. Nat Rev Nephrol 2017; 13: 115-131
• 11 Ivanova E, De Leo MG, De Matteis MA. et al. Cystinosis: clinical presentation, pathogenesis and treatment. Pediatr Endocrinol Rev 2014; 12 (Suppl. 01) S176-S184
• 12 Gahl WA, Kuehl EM, Iwata F. et al. Corneal crystals in nephropathic cystinosis: natural history and treatment with cysteamine eyedrops. Mol Genet Metab 2000; 71: 100-120
• 13 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
• 14 Kaiser-Kupfer MI, Fujikawa L, Kuwabara T. et al. Removal of corneal crystals by topical cysteamine in nephropathic cystinosis. N Engl J Med 1987; 316: 775-779
• 15 Liang H, Baudouin C, Tahiri Joutei Hassani R. et al. Photophobia and corneal crystal density in nephropathic cystinosis: an in vivo confocal microscopy and anterior-segment optical coherence tomography study. Invest Ophthalmol Vis Sci 2015; 56: 3218-3225
• 16 Pinxten AM, Hua MT, Simpson J. et al. Clinical Practice: A Proposed Standardized Ophthalmological Assessment for Patients with Cystinosis. Ophthalmol Ther 2017; 6: 93-104
• 17 Elder MJ, Astin CL. Recurrent corneal erosion in cystinosis. J Pediatr Ophthalmol Strabismus 1994; 31: 270-271
• 18 Tsilou ET, Rubin BI, Reed GF. et al. Age-related prevalence of anterior segment complications in patients with infantile nephropathic cystinosis. Cornea 2002; 21: 173-176
• 19 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
• 20 Wilmer MJ, Schoeber JP, van den Heuvel LP. et al. Cystinosis: practical tools for diagnosis and treatment. Pediatr Nephrol 2011; 26: 205-215
• 21 Kleta R, Blair SC, Bernardini I. et al. Keratopathy of multiple myeloma masquerading as corneal crystals of ocular cystinosis. Mayo Clin Proc 2004; 79: 410-412
• 22 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
• 23 Labbé 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
• 24 Elmonem MA, Veys KR, Soliman NA. et al. Cystinosis: a review. Orphanet J Rare Dis 2016; 11: 47
• 25 Shams F, Livingstone I, Oladiwura D. et al. Treatment of corneal cystine crystal accumulation in patients with cystinosis. Clin Ophthalmol 2014; 8: 2077-2084
• 26 Labbé A, Baudouin C, Deschenes G. et al. A new gel formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis: the Cystadrops OCT-1 study. Mol Genet Metab 2014; 111: 314-320
• 27 Castro-Balado A, Mondelo-Garcia C, Varela-Rey I. et al. Recent Research in Ocular Cystinosis: Drug Delivery Systems, Cysteamine Detection Methods and Future Perspectives. Pharmaceutics 2020; 12: 1177
• 28 Ariceta G, Camacho JA, Fernandez-Obispo M. et al. Cystinosis in adult and adolescent patients: Recommendations for the comprehensive care of cystinosis. Nefrologia 2015; 35: 304-321
• 29 Ariceta G, Lara E, Camacho JA. et al. Cysteamine (Cystagon^®) adherence in patients with cystinosis in Spain: successful in children and a challenge in adolescents and adults. Nephrol Dial Transplant 2015; 30: 475-480
• 30 Deng SX, Kruse F, Gomes JAP. et al. Global Consensus on the Management of Limbal Stem Cell Deficiency. Cornea 2020; 39: 1291-1302
• 31 Giannaccare G, Versura P, Buzzi M. et al. Blood derived eye drops for the treatment of cornea and ocular surface diseases. Transfus Apher Sci 2017; 56: 595-604
• 32 Odaka A, Toshida H, Ohta T. et al. Efficacy of retinol palmitate eye drops for dry eye in rabbits with lacrimal gland resection. Clin Ophthalmol 2012; 6: 1585-1593