Our current understanding of clinical characteristics and the genetics of patients with albinism

Figures & data

Figure 1. Staging schemes in albinism. Iris transillumination. Anterior segment photos in albinism show various degrees of iris transillumination according to the grading scheme by Summers et al. [17]. Adapted and reprinted with permission from Papageorgiou et al [18].

(a) Grading of fundus hypopigmentation in albinism (modified from Summers et al.) [17] Adapted and reprinted with permission from Papageorgiou et al. [18].

(b) Grading of foveal hypoplasia in albinism according to the grading scheme by Thomas et al. [19]. Adapted and reprinted with permission from Papageorgiou et al. [18].

Figure 2. Schematic drawing of the leicester grading system for Foveal Hypoplasia using OCT, shows a normal fovea, followed by typical and atypical grades of foveal hypoplasia. The normal fovea features outward displacement, termed extrusion, of the plexiform layers.

All grades of foveal hypoplasia feature continuation of the plexiform layers.

Grade 1a foveal hypoplasia is associated with a nearly normal pit resembling a ‘V’ shape and outer segment (OS) lengthening, and outer nuclear layer (ONL) widening relative to the parafoveal OS and ONL lengths, respectively.

Grade 1b foveal hypoplasia is associated with a shallow indent and OS lengthening and ONL widening relative to the parafoveal OS and ONL lengths, respectively.

In grade 2 foveal hypoplasia, all features of grade 1 are present except that no pit is present.

Grade 3 foveal hypoplasia represents all features of grade 2, except no lengthening of the OS segment is present.

Grade 4 foveal hypoplasia represents grade 3, except no ONL widening at the fovea (fovea plana) is present.

Atypical foveal hypoplasia is characterized by a shallow foveal pit and disruption of the inner segment ellipsoid (ISe) band forming a hyporeflective zone.

Abbreviations: ELM, external limiting membrane; GCL, ganglion cell layer; ILM, internal limiting membrane; INL, inner nuclear layer; IPL, inner plexiform layer; OPL, outer plexiform layer; RNFL, retinal nerve fiber layer; RPE, retinal pigment epithelium.

Reprinted with permission from Thomas MG, Kumar A, Mohammad S, et al. Structural grading of foveal hypoplasia. Ophthalmology. 2011;118(8):1653–1660. Copyright © 2011 Elsevier [19].

Figure 3. Multichannel VEPs to investigate intracranial visual pathway dysfunction (a and b).

Monocular stimulation is achieved by occluding one eye and presenting a pattern stimulus (checkerboard stimulus). Four lateral electrodes (1 and 2 on left occiput, 4 and 5 on the right occiput) and one midline electrode (electrode 3) are used. Five raw traces corresponding to the polarity of each electrode are obtained during monocular stimulation. In order to improve signal to noise, VEP traces shown are based on the polarity differences between the electrodes placed on the left and right occiput and obtained after averaging.

Individuals with a normal visual pathway would not have any significant difference in the polarity between the corresponding lateral electrodes (1 vs 5 or 2 vs 4).

In patients with idiopathic infantile nystagmus (IIN), there was no significant polarity differences in subtracted waveforms (1–5 and 2–4). R1-5 and L1-5 refers to traces that correspond to the difference in polarity between the corresponding lateral electrodes of 1 vs 5 of the right eye and left eye respectively. R2-4 and L2-4 refers to traces that correspond to the difference in polarity between the corresponding lateral electrodes of 2 vs 4 of the right eye and left eye respectively.

However, in a patient with chiasmal misrouting as seen in albinism, asymmetric responses are seen (blue arrows). R1-5 and L1-5 refers to traces that correspond to the difference in polarity between the corresponding lateral electrodes of 1 vs 5 of the right eye and left eye respectively. R2-4 and L2-4 refers to traces that correspond to the difference in polarity between the corresponding lateral electrodes of 2 vs 4 of the right eye and left eye respectively.

Adapted and reprinted under CC-BY license with permission from Thomas MG, Maconachie GD, Sheth V, McLean RJ, Gottlob I. Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing. European Journal of Human Genetics. 2017 Jun;25(6):725-34 [43].

Figure 4. In evaluating patients with suspected albinism, the outline of investigations, characteristic sign that should be elicited with each investigative modality and differential diagnoses are shown.

Abbreviations: EMR, eye movement recordings; FHONDA, foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis; IIN, idiopathic infantile nystagmus; OA, ocular albinism; OCA, oculocutaneous albinism; ONH, optic nerve hypoplasia.

Reprinted with permission from Liu S, Kuht HJ, Moon EH, Maconachie GDE, Thomas MG. Current and emerging treatments for albinism. Surv Ophthalmol 2021; 66: 362-377 [44].

Table 1. Classification of non-syndromic subtypes of albinism by gene.

OCA/OA disorders	Gene	Chromosome localization	Size	Descriptions
OCA1	TYR	11q14.3	65kb	OCA1A: absence of tyrosinase activity causing severe reduction of retinal, iris and skin pigmentation. OCA1B: also called ‘yellow’ OCA, reduced tyrosinase activity causing variable amount of pigmentation, with near normal cutaneous and hair pigment.
OCA2	OCA2 (p gene)	15q11.2-q12	345kb	Also called ‘brown’ OCA. Variants of OCA2 are more common in sub-Saharan Africa.
OCA3	TYRP1	9p23	17kb	Also called ‘red’ or ‘rufous’ OCA. Characterized by red-bronze skin color, ginger-red hair and blue/brown irises. More common among African populations.
OCA4	SLC45A2	5p13.3	40kb	Cutaneous and ocular hypopigmentation with normal visual acuity and foveal structure [15]. Most common OCA in Japan, about 25–27% of cases [45].
OCA5	Unknown	4q24	3.84Mb	White skin, golden hair, photophobia, nystagmus, foveal hypoplasia and impaired visual acuity. Reported in a consanguineous Pakistani family [7].
OCA6	SLC24A5	15q21	Unknown	Skin is typically hypopigmented with some ability to become tan. Hair color ranges from white to brown [46].
OCA7	LRMDA	10q22	Unknown	Significant overlap of phenotypes of other OCAs. Initially reported in a Faroese cohort [47].
OCA8	DCT	13q32.1	Unknown	Mild hair and skin hypopigmentation, nystagmus, iris transillumination and retina hypopigmentation [48]. Rare.
OA	GPR143	Xp22.3e22.2	Unknown	Only ocular hypopigmentation is present. Carriers have ‘mud-splattered‘ fundus.
FHONDA	SLC38A8	16q23.3	Unknown	Absent hypopigmentation but ocular features of foveal hypoplasia, nystagmus and optic nerve misrouting are severe.

OCA, oculocutaneous albinism; OA, ocular albinism.

Table 2. Genes involved in different syndromic OCAs.

Syndromic OCA	Chromosome	Gene(s)	Pathophysiology	Description
Hermansky-Pudlak syndrome	Chr 10	AP3B1 AP3D1 BLOC1S3 BLOC1S5 BLOC1S6 DTNBP1 HPS1 HPS3 HPS4 HPS5 HPS6	Impaired melanosome formation, trafficking or transfer to keratinocytes	Increased incidence in people of Puerto-Rican ancestry Ocular and cutaneous features: infantile nystagmus, variable hypopigmentation of skin and hair, grade 3 & 4 foveal hypoplasia Systemic features: Bleeding diathesis, low platelets, pulmonary fibrosis, granulomatous colitis.
Chediak-Higashi syndrome	Chr 1	LYST	Abnormal protein trafficking	Ocular and cutaneous features: mild OCA with less severe hypopigmentation. Systemic features: leucocyte abnormalities, immunodeficiency, recurrent pyogenic infection.

OCA, oculocutaneous albinism; Chr, Chromosome.

Summers CG, Knobloch WH, Witkop CJJ, et al. Hermansky-pudlak syndrome. Ophthalmic Findings Ophthalmology. 1988;95(4):545–554. doi: 10.1016/S0161-6420(88)33152-0

 PubMed Web of Science ®Google Scholar

Papageorgiou E, McLean RJ, Gottlob I. Nystagmus in childhood. Pediatr Neonatol. 2014;55(5):341–351. doi: 10.1016/j.pedneo.2014.02.007

 PubMed Web of Science ®Google Scholar

Thomas MG, Kumar A, Mohammad S, et al. Structural grading of foveal hypoplasia using spectral-domain optical coherence tomography a predictor of visual acuity? Ophthalmol. 2011;118(8):1653–1660. doi: 10.1016/j.ophtha.2011.01.028

 PubMed Web of Science ®Google Scholar

Thomas MG, Maconachie GD, Sheth V, et al. Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing. Eur J Hum Genet. 2017;25(6):725–734. doi: 10.1038/ejhg.2017.44

 PubMed Web of Science ®Google Scholar

Liu S, Kuht HJ, Moon EH, et al. Current and emerging treatments for albinism. Surv Ophthalmol. 2021;66(2):362–377. doi: 10.1016/j.survophthal.2020.10.007

 PubMed Web of Science ®Google Scholar

Hayashi M, Suzuki T. Oculocutaneous albinism type 4. Adam MP, Feldman J, Mirzaa GM, et al., editors. Seattle (WA): University of Washington, Seattle; 1993. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

 Google Scholar

Okamura K, Suzuki T. Current landscape of Oculocutaneous Albinism in Japan. Pigment Cell Melanoma Res. 2021;34(2):190–203. doi: 10.1111/pcmr.12927

 PubMed Web of Science ®Google Scholar

Kausar T, Bhatti MA, Ali M, et al. OCA5, a novel locus for non-syndromic oculocutaneous albinism, maps to chromosome 4q24. Clin Genet. 2013;84(1):91–93. doi: 10.1111/cge.12019

 PubMed Web of Science ®Google Scholar

Wei AH, Zang DJ, Zhang Z, et al. Exome sequencing identifies SLC24A5 as a candidate gene for nonsyndromic oculocutaneous albinism. J Invest Dermatol. 2013 Jul 1;133(7):1834–40. doi: 10.1038/jid.2013.49

 PubMed Web of Science ®Google Scholar

Grønskov K, Dooley CM, Østergaard E, et al. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism. Am J Hum Genet. 2013 Mar 7;92(3):415–21. doi: 10.1016/j.ajhg.2013.01.006

 PubMed Web of Science ®Google Scholar

Pennamen P, Tingaud-Sequeira A, Gazova I, et al. Dopachrome tautomerase variants in patients with oculocutaneous albinism. Genet Med. 2021 Mar 1;23(3):479–87. doi: 10.1038/s41436-020-00997-8

 PubMed Web of Science ®Google Scholar