Author: Lucia Lee Ferraro (Spain)
Co-authors: Imma Hernan, Marc Biarnés, Míriam Garcia, Miguel Carballo, Jordi Monés
Purpose
Choroideremia is the most common X-linked choroidal dystrophy, with an estimated prevalence of 1:50.000 people. It is caused by mutations in the CHM gene on Xq21.2. The gene encodes REP-1 (Rab escort protein-1), which is involved in intracellular trafficking. The symptoms are very similar of those with retinitis pigmentosa, with young males presenting night blindness and progressive loss of peripheral visual fields eventually leading to legal blindness after the fifth decade. Female carriers may have mild or moderate signs of the disease visible in color fundus photography (CFP) and fundus autofluorescence (FAF), usually with few symptoms. It is generally non-syndromic, but some exceptions can occur. No treatment is available, but there are a few ongoing trials using gene therapy. The purpose of this article is to describe the functional, structural and genetic findings and their implications in a patient with choroideremia and his family.
Setting/Venue
Patients were visited between March and April 2021 at the Institut de la Màcula (Hospital Quirón Teknon), a tertiary retina referral center in Barcelona, Spain.
Methods
The molecularly confirmed diagnosis of choroideremia in a 23-year-old male with hearing loss and mild intellectual disability prompted the cascade exam of ten relatives. Patients underwent a complete ophthalmic exams including functional (best-corrected visual acuity [BCVA] with ETDRS charts) and structural (CFP, FAF and SD-OCT) testing. In addition, 24-2 static perimetry, 9-field CFP and FAF imaging and OCT angiography were conducted in subjects with lesions suggestive of a carrier status. To study the presence of pathogenic variants in the CHM gene, molecular analysis of all family members was performed. First, multiplex ligation-dependent probe amplification (MLPA) analysis using P366 CHM-RP2-RPGR SALSA MLPA probe mix was employed to detect possible deletions or duplications in the CHM gene. Afterwards, to characterize the size and breakpoints of the detected deletion, the DNA of the index case was analyzed by comparative genomic hybridization (CGH)-array.
Results
Clinical findings in the index case included bilateral degeneration of the choroid, retinal pigment epithelium (RPE) and photoreceptors sparing the macula, with normal looking vessels and absence of optic disc pallor. Perimetry showed marked constriction of the visual field. His mother and two sisters showed features on CFP and FAF characteristic of choroideremia carriers, but their perimetry was unremarkable. The index case carried a complete deletion of CHM gene according to the ratios of the MLPA analysis. Moreover, the three female suspected carriers were heterozygous for the deletion. No other family members were affected. The grandmother of the index case was not affected and the grandfather was asymptomatic. Therefore, this implied a de novo mutation in the mother’s proband. CGH-array technique allowed delimitation of the deletion and implicated genes.
Conlusions
The signs and symptoms in the index case, with peripheral alterations of the RPE, nyctalopia, visual field constriction and hearing loss guided the diagnosis of several specialists towards Usher syndrome. However, no mutations related to this disease were found. Most choroideremia cases are non-syndromic but complete deletion of CHM may more frequently be associated with systemic involvement and rarely cause hearing loss and intellectual impairment. Therefore, choroideremia must be considered in the differential diagnosis of Usher syndrome. Given that choroideremia is an X-linked recessive condition, it is very important to know which family members, especially women of childbearing age, are carriers of this mutation. FAF has shown to be a sensible exam for identifying disease carriers but to confirm the results, genetic testing and counselling are highly recommended. Confirmation of the mutation in carriers allows the possibility of preimplantation diagnoses in patients that are planning a pregnancy.
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