Clinical spectrum of choroideremia in pediatric carriers of CHM gene mutations

Background. Choroideremia (CHM, OMIM 303100) is a rare (1 in 50,000 males) hereditary bilateral retinal dystrophy with an X-linked recessive inheritance pattern. The disease leads to progressive vision loss due to the primary degeneration of the choriocapillaris, followed by progressive atrophy of the retinal pigment epithelium (RPE) and photoreceptors. Female carriers of pathogenic variants in the CHM gene may also manifest clinical symptoms. Purpose: to present the phenotypic characteristics of choroideremia in pediatric carriers of a CHM gene mutation. Materials and methods. This article describes a clinical case of choroideremia associated with a CHM gene mutation in two sisters aged 4 and 2 years. The parents consulted an ophthalmologist due to complaints of reduced distance vision in the elder daughter. In addition to standard ophthalmologic examination, both patients underwent spectral-domain optical coherence tomography (SD-OCT) and electrophysiological testing (ERG). Molecular genetic testing was conducted for diagnostic confirmation and detection of the pathogenic nucleotide variant, preceded by collection of family history. Results. A detailed pedigree analysis and comprehensive examination of biological relatives across three generations confirmed an X-linked mode of inheritance of the disease. Best-corrected visual acuity (BCVA) in both girls was 0.9. The high visual acuity correlated with the preserved foveal architecture observed on spectral-domain optical coherence tomography (SD-OCT), which demonstrated an intact trilaminar structure comprising Bruch’s membrane, the retinal pigment epithelium (RPE), and the external limiting membrane. The ellipsoid zone (EZ), corresponding to the junction between the inner and outer segments of photoreceptors, was absent in the peripheral retina but remained preserved within the foveal region. Electrophysiological evaluation was limited due to the young age of the patients. Molecular genetic testing of family members revealed a previously unreported pathogenic variant in exon 10 of the CHM gene, resulting in a premature stop codon at position 445 (p.Ser445*) in a hemizygous state. This variant is consistent with the molecular characteristics of choroideremia, a form of inherited retinal degeneration (IRD). Conclusion. An etiopathogenetic diagnostic approach and molecular genetic testing enabled the accurate identification of the specific IRD subtype–choroideremia. Pediatric carriers of the pathogenic variant in exon 10 of the CHM gene may exhibit early signs of chorioretinal degeneration, detectable by OCT and ERG.

1. Shcherbatova OI, Zueva MV. Hereditary diseases of the choroid. In: Shamshinovа AM, ed. Hereditary and congenital retinal diseases. Moscow: Meditsina; 2001. P. 447–455. (In Russ.)

2. Shamshinova AM, Zolnikova IV. Molecular basis of hereditary retinal diseases. Medical genetics. 2004;4:160–169. (In Russ.)

3. Smith JM, Steel D. Retinitis pigmentosa. BMJ. 2004;328(7443):442–444. doi: 10.1136/bmj.328.7443.442

4. Testa F, Rossi S, Colucci R, et al. Macular abnormalities in Italian patients with retinitis pigmentosa. Br J Ophthalmol. 2014;98(7):946–950. doi: 10.1136/bjophthalmol-2013-304017

5. Aleman TS, Cideciyan AV, Sumaroka A, et al. Retinal laminar architecture in human retinitis pigmentosa caused by Rhodopsin gene mutations. Invest Ophthalmol Vis Sci. 2008;49(4):1580–1590. doi: 10.1167/iovs.07-1110

6. Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010;29(5):335–375. doi: 10.1016/j.preteyeres.2010.03.001

7. Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis pigmentosa. Clin Genet. 2013;84(2):132–141. doi: 10.1111/cge.12203

8. Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368(9549):1795–1809. doi: 10.1016/S0140-6736(06)69740-7

9. Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012;130(1):9–24. doi: 10.1001/archophthalmol.2011.298

10. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008;358(21):2240–2248. doi: 10.1056/NEJMoa0802315

11. Parmeggiani F, Sorrentino FS, Ponzin D, et al. Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics. 2011;12(4):238–249. doi: 10.2174/138920211795677912

12. Pierce EA, Bennett J. The status of RPE65 gene therapy trials: safety and efficacy. Cold Spring Harb Perspect Med. 2015;5(8):a017285. doi: 10.1101/cshperspect.a017285

13. Sharon D, Blackshaw S, Cepko CL, Dryja TP. Profile of the genes expressed in the human peripheral retina, macula, and retinal pigment epithelium determined through serial analysis of gene expression (SAGE). Proc Natl Acad Sci U S A. 2002;99(1):315–320. doi: 10.1073/pnas.012582799

14. Dunaief JL, Dentchev T, Ying GS, Milam AH. The role of apoptosis in age-related macular degeneration. Arch Ophthalmol. 2002;120(11):1435–1442. doi: 10.1001/archopht.120.11.1435

15. Ferrington DA, Sinha D, Kaarniranta K. Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration. Prog Retin Eye Res. 2016;51:69–89. doi: 10.1016/j.preteyeres.2015.08.002

16. Gehrs KM, Anderson DH, Johnson LV, Hageman GS. Age-related macular degeneration-emerging pathogenetic and therapeutic concepts. Ann Med. 2006;38(7):450–471. doi: 10.1080/07853890600946759

17. Lim LS, Mitchell P, Seddon JM, et al. Age-related macular degeneration. Lancet. 2012;379(9827):1728–1738. doi: 10.1016/S0140-6736(12)60282-7

18. Pascolini D, Mariotti SP, Pokharel GP, et al. 2002 global update of available data on visual impairment: a compilation of population-based prevalence studies. Ophthalmic Epidemiol. 2004;11(2):67–115. doi: 10.1076/opep.11.2.67.29135

19. Ratnapriya R, Chew EY. Age-related macular degeneration-clinical review and genetics update. Clin Genet. 2013;84(2):160–166. doi: 10.1111/cge.12219

20. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106–116. doi: 10.1016/S2214-109X(13)70145-1

21. Yu J, Ni Y, Keane PA, et al. Foveal avascular zone area and parafoveal vessel density measurements in different stages of diabetic retinopathy by optical coherence tomography angiography. Invest Ophthalmol Vis Sci. 2016;57(9):324–31. doi: 10.1167/iovs.15-18647.