PURPOSE: Danon disease (DD) is a rare X-linked disorder caused by pathogenic variants in LAMP2. DD primarily manifests as a severe cardiomyopathy. An early diagnosis is crucial for patient survival. The aim of the study was to determine the usefulness of ocular examination for identification of DD. METHODS: Detailed ocular examination in 10 patients with DD (3 males, 7 females) and a 45-year-old asymptomatic female somatic mosaic carrier of a LAMP2 disease-causing variant. RESULTS: All patients with manifest cardiomyopathy had pigmentary retinopathy with altered autofluorescence and diffuse visual field loss. Best corrected visual acuity (BCVA) was decreased (<0.63) in 8 (40%) out of 20 eyes. The severity of retinal pathology increased with age, resulting in marked cone-rod involvement overtime. Spectral-domain optical coherence tomography in younger patients revealed focal loss of photoreceptors, disruption and deposition at the retinal pigment epithelium/Bruch's membrane layer (corresponding to areas of marked increased autofluorescence), and hyperreflective foci in the outer nuclear layer. Cystoid macular oedema was seen in one eye. In the asymptomatic female with somatic mosaicism, the BCVA was 1.0 bilaterally. An abnormal autofluorescence pattern in the left eye was present; while full-field electroretinography was normal. CONCLUSIONS: Detailed ocular examination may represent a sensitive and quick screening tool for the identification of carriers of LAMP2 pathogenic variants, even in somatic mosaicism. Hence, further investigation should be undertaken in all patients with pigmentary retinal dystrophy as it may be a sign of a life-threatening disease.

2nd Department of Medicine Department of Cardiovascular Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Cardiology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Ophthalmology Faculty of Medicine in Hradec Kralove Charles University and University Hospital Hradec Kralove Hradec Kralove Czech Republic

Department of Paediatric Haematology and Oncology Childhood Leukaemia Investigation Prague 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Paediatrics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Institute of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Moorfields Eye Hospital NHS Foundation Trust London UK

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

UCL Institute of Ophthalmology University College London London UK

Zobrazit více v PubMed

Amos-Landgraf JM, Cottle A, Plenge RM, Friez M, Schwartz CE, Longshore J & Willard HF (2006): X chromosome-inactivation patterns of 1,005 phenotypically unaffected females. Am J Hum Genet 79: 493-499.

Bach M, Brigell MG, Hawlina M, Holder GE, Johnson MA, McCulloch DL, Meigen T & Viswanathan S (2013): ISCEV Standard for clinical pattern electroretinography (PERG): 2012 update. Doc Ophthalmol 126: 1-7.

Boucek D, Jirikowic J & Taylor M (2011): Natural history of Danon disease. Genet Med 13: 563-568.

Brambatti M, Caspi O, Maolo A, Koshi E, Greenberg B, Taylor MRG & Adler ED (2019): Danon disease: Gender differences in presentation and outcomes. Int J Cardiol 286: 92-98.

Chen XL, Zhao Y, Ke HP, Liu WT, Du ZF & Zhang XN (2012): Detection of somatic and germline mosaicism for the LAMP2 gene mutation c.808dupG in a Chinese family with Danon disease. Gene 507: 174-176.

Chi C, Leonard A, Knight WE et al. (2019): LAMP-2B regulates human cardiomyocyte function by mediating autophagosome-lysosome fusion. Proc Natl Acad Sci USA 116: 556-565.

Fukushima M, Inoue T, Miyai T & Obata R (2020): Retinal dystrophy associated with Danon disease and pathogenic mechanism through LAMP2-mutated retinal pigment epithelium. Eur J Ophthalmol, 30(3), 570-578.

Hood DC, Bach M, Brigell M et al. (2012): ISCEV Standard for clinical multifocal electroretinography (mfERG) (2011 edition). Doc Ophthalmol 124: 1-13.

Invernizzi A, Pellegrini M, Acquistapace A et al. (2018): Normative data for retinal-layer thickness maps generated by spectral-domain OCT in a white population. Ophthalmol Retina 2: 808-815.

Mack HG (2014): Cystoid macular edema in a patient with Danon disease. Indian J Ophthalmol 62: 1161-1163.

Majer F, Vlaskova H, Krol L et al. (2012): Danon disease: a focus on processing of the novel LAMP2 mutation and comments on the beneficial use of peripheral white blood cells in the diagnosis of LAMP2 deficiency. Gene 498: 183-195.

Majer F, Pelak O, Kalina T et al. (2014): Mosaic tissue distribution of the tandem duplication of LAMP2 exons 4 and 5 demonstrates the limits of Danon disease cellular and molecular diagnostics. J Inherit Metab Dis 37: 117-124.

Majer F, Piherova L, Reboun M et al. (2018): LAMP2 exon-copy number variations in Danon disease heterozygote female probands: Infrequent or underdetected? Am J Med Genet A 176: 2430-2434.

Majer F, Kousal B, Dusek P et al. (2019): Alu-mediated Xq24 deletion encompassing CUL4B, LAMP2, ATP1B4, TMEM255A, and ZBTB33 genes causes Danon disease in a female patient. Am J Med Genet A 182: 219-223.

McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R & Bach M (2015): ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol 130: 1-12.

Meinert M, Englund E, Hedberg-Oldfors C, Oldfors A, Kornhall B, Lundin C & Wittström E (2019): Danon disease presenting with early onset of hypertrophic cardiomyopathy and peripheral pigmentary retinal dystrophy in a female with a de novo novel mosaic mutation in the LAMP2 gene. Ophthalmic Genet 40: 227-236.

Notomi S, Ishihara K, Efstathiou NE et al. (2019): Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina. Proc Natl Acad Sci USA 116: 23724-23734.

Prall FR, Drack A, Taylor M, Ku L, Olson JL, Gregory D, Mestroni L & Mandava N (2006): Ophthalmic manifestations of Danon disease. Ophthalmology 113: 1010-1013.

Rowland TJ, Sweet ME, Mestroni L & Taylor MR (2016): Danon disease - dysregulation of autophagy in a multisystem disorder with cardiomyopathy. J Cell Sci 129: 2135-2143.

Schorderet DF, Cottet S, Lobrinus JA, Borruat FX, Balmer A & Munier FL (2007): Retinopathy in Danon disease. Arch Ophthalmol 125: 231-236.

Shoji T, Sakurai Y, Chihara E, Nishikawa S & Omae K (2009): Reference intervals and discrimination values of the Lanthony desaturated D-15 panel test in young to middle-aged Japanese army officials: the Okubo Color Study Report 1. Eye (Lond) 23: 1329-1335.

Sikora J, Majer F & Kalina T (2015): LAMP2 flow cytometry in peripheral white blood cells is an established method that facilitates identification of heterozygous Danon disease female patients and mosaic mutation carriers. J Cardiol 66: 88-89.

Strong S, Liew G & Michaelides M (2017): Retinitis pigmentosa-associated cystoid macular oedema: pathogenesis and avenues of intervention. Br J Ophthalmol 101: 31-37.

Thiadens AA, Slingerland NW, Florijn RJ, Visser GH, Riemslag FC & Klaver CC (2012): Cone-rod dystrophy can be a manifestation of Danon disease. Graefes Arch Clin Exp Ophthalmol 250: 769-774.

Thompson DA, Constable PA, Liasis A, Walters B & Esteban MT (2016): The physiology of the retinal pigment epithelium in Danon disease. Retina 36: 629-638.

Wu H, Luo J, Yu H et al. (2014): Cellular resolution maps of X chromosome inactivation: implications for neural development, function, and disease. Neuron 81: 103-119.