Colour vision deficiency and inherited retinal disease: Viva

This is a branching oral built to probe the reasoning that holds the colour vision test and the inheritance at the centre, the electroretinography and the molecular genetics of the inherited retinal disease, and to expose the candidate who has memorised the headline of the gene therapy without the safety-critical corners. The questions escalate from the framing to the Ishihara test, the inheritance, the retinitis pigmentosa and the Leber congenital amaurosis, with deliberate probes into the choroideremia and the gene therapy. [6]

Opening question: framing the problem

The examiner opens with the boy who confuses the red and the green and asks: how do you frame this problem, and what is your first step? [6]

A strong answer names the congenital red-green colour vision deficiency, confirms the finding with the formal Ishihara test, and states that the first step is the exclusion of the acquired cause and the reassurance. [6]

Model answer. This boy has the congenital red-green colour vision deficiency, the common X-linked recessive trait, and the first step is to confirm it with the formal Ishihara test, to exclude the acquired cause by confirming the normal acuity, the full fields and the healthy fundus, and to reassure the family that the condition is stable, inherited and benign. The normal acuity and the healthy fundus distinguish it from the acquired defect and the inherited retinal dystrophy. [6]

Probe one: the Ishihara test

The examiner presses: describe the Ishihara test, and tell me its limitation. [6]

A strong answer describes the technique and the limitation. The test is performed in the good room light, with the plates held at the comfortable reading distance of about seventy-five centimetres, and the child names the number on each plate. The normal child reads twelve or more of the fourteen screening plates, and the child with the red-green defect misreads the plates in the pattern that distinguishes the protan from the deutan. The limitation is the blue-yellow tritan defect, which the Ishihara is poor at detecting and which the Hardy-Rand-Rittler plates and the Farnsworth tests detect better, with the anomaloscope as the gold standard. [6][2]

Pitfall probe. When would the tritan defect point away from the congenital cause? The acquired tritan defect points to the optic neuropathy, the macular disease or the drug toxicity, because the congenital tritan defect is rare, and the new and the progressive blue-yellow change demands the referral and the workup of the acquired cause. [6]

Probe two: the inheritance

The examiner asks: what is the inheritance, and what is the prevalence? [6]

A strong answer names the X-linked recessive trait of the OPN1LW and the OPN1MW opsin genes on the X chromosome, the prevalence of roughly one in twelve males and well under one percent of the females, and the deuteranomaly as the commonest form. The mother is the carrier and the son is the affected male, and the global review of Birch showed the fairly constant prevalence across the populations. [6][8]

Pitfall probe. Why are the carrier females so rarely affected? Because the random X-inactivation leaves, on the average, one functional copy of the opsin gene in enough of the retinal cones to preserve the colour vision, which is the Lyonisation that protects the female. [8]

Branch one: the progressive night blindness

The examiner pivots: imagine instead a child with the progressive night blindness and the field loss. What is this, and how do you confirm it? [1]

A strong answer names the retinitis pigmentosa, the rod-cone dystrophy, presenting with the night blindness and the gradual constriction of the field. The confirmation is the fundus, which shows the bone-spicule pigmentation, the attenuated arterioles and the waxy pallor of the disc, and the electroretinography, which shows the extinguished rod response. The inheritance is the autosomal dominant in the RHO form, the autosomal recessive in the USH2A form and the X-linked in the severe RPGR form, and the syndromic forms include the Usher syndrome with the deafness and the Bardet-Biedl syndrome. [1][2]

Pitfall probe. What two syndromes must you exclude in the child with the retinitis pigmentosa? The Usher syndrome, the retinitis pigmentosa with the congenital or the early sensorineural deafness, and the Bardet-Biedl syndrome, the retinitis pigmentosa with the obesity, the polydactyly, the renal anomaly and the learning difficulty, because the syndromic diagnosis changes the management and the counselling. [1]

Branch two: the infant with the nystagmus

The examiner pivots again: an infant presents with the nystagmus, the poor fixation and the near-absent electroretinography. What is this, and is there a treatment? [3]

A strong answer names the Leber congenital amaurosis, the severe congenital retinal dystrophy, and the treatable RPE65 form. The molecular genetic testing by the next-generation panel identifies the biallelic RPE65 mutation, and the voretigene neparvovec is the approved gene therapy, a single subretinal injection of the adeno-associated virus vector carrying the normal RPE65 gene into each eye. The Russell phase three trial showed the improvement of the functional vision on the multi-luminance mobility test, and it secured the first approval of a gene therapy for an inherited disease. [3][9][11]

Pitfall probe. Is the gene therapy a cure for all the Leber congenital amaurosis? No, it is reserved for the biallelic RPE65 form with the viable retinal cells, and it does not apply to the other genes, and it improves the functional vision rather than the full restoration of the sight, which is the honest counselling of the family. [3][11]

Branch three: the X-linked family

The examiner closes: a boy has the X-linked family history of the progressive sight loss and the chorioretinal atrophy. What is this, and who else needs the testing? [8]

A strong answer names the choroideremia, the X-linked recessive defect of the CHM gene, presenting with the night blindness and the progressive chorioretinal atrophy of the mid-periphery in the male, and the MacLaren gene therapy trial that opened the frontier. The mother and the sisters are the carrier females, and the genetic counselling and the testing of the family is the management, alongside the contrast with the X-linked retinoschisis of the RS1 gene, which presents with the foveal schisis of the young boy. [8][11]