In this report, we describe for the first time three unrelated Dutch OCA4 patients, with evident hypopigmentation of skin, hair, and iris, but normal visual acuity, foveal development and routing of the visual pathways. Both missense mutations found in P1, c.1502C > A; p.(Ala501Asp) and c.1567G > A; p.(Ala523Thr), are localized in the major facilitator superfamily domain. c.1502C > A. The p.(Ala501Asp) variant was previously reported in two heterozygous albinism patients, one was severely affected (not specified) and the other patient had mild hypopigmentation and nystagmus (further details missing).7,24 The second mutation, c.1567G > A; p.(Ala523Thr), was described in one compound heterozygous albinism patient without phenotypic description.37 The missense variants c.125T > C and c.310C > T found in P2 predict the amino acid substitution p.(Met42Thr) and p.(Pro104Ser) respectively, changing a highly conserved amino acid. The second mutation c.310C > T; p.(Pro104Ser) was novel. P3 had one previously reported mutation, c.1082T > C; p.(Leu361Pro), and one novel mutation, c.1368 + 3_1368 + 9del p.(?). The missense mutation c.1082T > C; p.(Leu361Pro) has been reported in a homozygous patient that was severely affected in melanin synthesis and visual function.25 The mutation was also found in severely affected P4 and P5 from our series. The novel variant c.1368 + 3_1368 + 9del p.(?) probably results in abnormal splicing of the SLC45A2 RNA, causing a frameshift by skipping exon 6. The pathological significance of the novel mutations has to be further investigated.
Unravelling the genotypic profile of all these cases does not provide a decisive clue for the variety in phenotypic presentation in this cohort. It is remarkable, that in our series of nine OCA4 patients, all patients showed obvious lack of pigmentation of skin, hair, and eyes. But, concerning visual function and ocular development, they were either on the poorer end of the spectrum for albinism, or were not affected at all.
Since the first patient reported in 2001, many patients with OCA4 are reported. In contrast to the homogeneous hypopigmentation phenotype we found in our cohort, in the literature the degree of pigmentation seems to vary from complete lack of pigmentation to very mild hypopigmentation.1,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29 While most reports describe pigmentation levels of skin and hair, ophthalmic details are usually scarce. Some studies report absence of nystagmus in some patients.8,9,12,14,16,17,18,19 Visual acuities in OCA4 patients in earlier reports ranged from − 0.1 to 1.5 logMAR, with most patients having poor VA.8,17, 25,5,38,13,15,24,27 Only three patients were described with normal VA, and all three had only mild or no hypopigmentation.8,17, 25 Rundshagen et al. described a patient with VA of 0.2 logMAR, subtle hypopigmentation, and nystagmus.25 The second patient with good VA was of Japanese origin. His VA was 0.0 logMAR, he had brown hair and mild hypopigmentation of the skin, with the ability to tan. Other ophthalmic details were missing.8 An Italian patient with good VA (< 0.2 logMAR), no nystagmus, minimal iris translucency, and no fundal hypopigmentation is the only OCA4 patient decribed, to our knowledge, without foveal hypoplasia. In this patient misrouting was present, and molecular analysis revealed two mutations in the SLC45A2 gene, c.619C4G (p.L207V) and c.606G4C (p.W202C).17 Until now, no patients have been described with evident lack of pigmentation of skin, hair, and eyes, but with normal ocular development, -i.e. normal VA, no nystagmus, no foveal hypoplasia and normal routing of the optic nerve fibers. Especially the absence of foveal hypoplasia is remarkable, occurring in less than 0.7% of albinism patients.1
It is still unclear why mutations in genes responsible for melanin synthesis cause defects in the development of the visual system. It is assumed that lack of melanin in the retinal pigment epithelium is responsible for excessive crossing of the optic nerve fibers and foveal hypoplasia. Pigment epithelium-derived factor (PEDF) is a negative regulator of angiogenesis and plays an important role in the formation of the foveal avascular zone.39 PEDF is decreased in the absence of tyrosinase, and therefore foveal hypoplasia could be caused by reduced PEDF.40,41 However, a role for PEDF in chiasmal misrouting has not been established.
Generally, albinism patients with more severe hypopigmentation have more severe foveal hypoplasia and worse visual acuity.1 Patients P4-P9 from this report conform to this phenotype. In contrast, P1, P2, and P3 demonstrate that normal foveal development, and normal routing of the optic nerve fibers can occur despite an evident lack of melanin. Non pathogenic variants in SLC45A5 may cause lightly pigmented skin and hair without an ocular phenotype. However, the variants found in P1, P2, and P3 were likely pathogenic, and importantly, the patients’ hypopigmented phenotype was not restricted to skin and hair, as they did have grade 3–4 iris translucency.
The OCA4 phenotype of patients P1, P2, and P3 seems the very opposite of the phenotype of the FHONDA syndrome, caused by mutations in SLC38A842,43,44,45. Patients with FHONDA have nystagmus, poor VA, severe foveal hypoplasia and misrouting, but no pigmentation defect. The FHONDA syndrome provided the first convincing evidence that lack of melanin is not the only determining factor in the combined occurrence of foveal hypoplasia and misrouting.
The three OCA4 patients with normal visual development we describe in this report, are further proof that the relationship between pigmentation defect and ocular deficits in albinism is more complicated than previously thought. Further research is needed to unravel the mechanisms that cause some OCA4 patients to have a severe albinism phenotype, while others do not show any ocular deficit, apart from iris translucency.