Phenotypic manifestations of choroideremia in carriers of a mutation in the CHM gene in childhood

Background. Choroideremia (CHM, OMIM303100) is a rare (1:50 000 men) hereditary disease, with an X-linked, recessive type of inheritance. Leads to significant loss of vision against the background of primary damage to the choriocapillary layer of the vascular membrane with subsequent progressive atrophy of the retinal pigment epithelium (RPE) and photoreceptors.
Purpose. To present the features of the phenotypic manifestations of choroideremia in carriers of a mutation in the CHM gene in childhood.
Methods. The article describes a clinical case of choroideremia with a mutation in the CHM gene in two sisters aged 4 and 6, whose parents went to an ophthalmologist complaining of decreased distant vision in their eldest daughter. In addition to the standard ophthalmological examination, patients underwent spectral OCT and electrophysiological examinations. To verify the diagnosis and identify the pathogenic nucleotide sequence of the gene, a molecular genetic study was performed with a preliminary collection of family history.
Results. A family history and a comprehensive examination of the blood relatives of this family in 3 generations established the Х-linked type of inheritance of the disease. The girls’ corrested visual acuity was 0.9. The high visual acuity of the patients correlated with the state of the fovea according to spectral OCT, which retained a three layered structure: the Bruch’s membrane – PES – the outer boundary membrane. The line of articulation of the outer and inner photoreceptors segments was absent on the periphery of the scan, but remained within the fovea. Electrophysiological examination was difficult due to the patients’ age. A genetic examination of the family members revealed a previously undescribed pathogenic variant of the nucleotide sequence in exon 10 of the CHM gene, leading to the appearance of a premature translation termination site in codon 445 (p.Ser445*) which is inherent in such a form of IRD as choroideremia.
Conclusion. Thus, the genetic examination made it possible to correctly verify the form of IRD – choroideremia. Carriers of the pathogenic variant of the nucleotide sequence in exon 10 of the CHM gene, even in childhood, have signs of chorioretinal degeneration, detected by OCT and electrophysiological data.

1. Shcherbatova O.I., Zueva M.V. Nasledstvennyye zabolevaniya khorioidei. V kn.: Shamshinova A.M., red. Nasledstvennyye i vrozhdennyye zabolevaniya setchatki i zritel’nogo nerva. [Hereditary diseases of the choroid. In: Shamshinovа AM, ed. Hereditary and congenital retinal diseases. Moscow: Meditsina]. 2001: 447–455 (In Russ.).

2. Shamshinova A.M., Zolnikova I.V. Molekulyarnyye osnovy nasledstvennykh degeneratsiy setchatki [Molecular basis of hereditary retinal diseases]. Meditsinskaya genetika [Medical genetics]. 2004;4:160–169 (In Russ.).

3. Smith J.M., 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 T.S., Cideciyan A.V., 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 S.P., Sullivan L.S., Bowne S.J. Genes and mutations causing retinitis pigmentosa. Clin Genet. 2013;84(2): 132-141. doi: 10.1111/cge.12203

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

9. Jacobson S.G., Cideciyan A.V., 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 A.M., 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 F.S., Ponzin D., et al. Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics. 2011;12(4): 238-249. doi: 10.2174/138920211795677912

12. Pierce E.A., 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 C.L., Dryja T.P. 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 J.L., Dentchev T., Ying G.S., Milam A.H. 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 D.A., 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 K.M., Anderson D.H., Johnson L.V., Hageman G.S. Agerelated macular degeneration--emerging pathogenetic and therapeutic concepts. Ann Med. 2006; 38(7): 450-471. doi: 10.1080/07853890600946759

17. Lim L.S., Mitchell P., Seddon J.M., Holz F.G., Wong T.Y. Agerelated macular degeneration. Lancet. 2012;379(9827): 1728-1738. doi: 10.1016/S0140-6736(12)60282-7

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

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

20. Wong W.L., 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 P.A., 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

22. Zhang X., Thibault G., Riviere J.B. Segmentation of retinal layers in OCT images of the peripapillary retina by a global phase-based method. Biomed Opt Express. 2011;2(1): 256-64. doi: 10.1364