Ophthalmological Manifestations of Oculocutaneous and Ocular Albinism: Current Perspectives

Figures & data

Figure 1 Schematic representation of melanin biosynthesis in the melanocyte. After synthesis and subsequent processing in the Golgi body - rough endoplasmic reticulum (ER) complex, tyrosinase and tyrosinase-related protein 1 (TYRP1) are trafficked to the developing melanosome via membrane transporter proteins P and MATP. Mutations in tyrosinase or in TYRP1 result in the retention of these mutant proteins in the ER, and these are subsequently degraded using proteasome mediated pathways. The rest of the tyrosinase and TYRP 1 proteins undergo endosomal/lysosomal proteolysis. Retinal pigment epithelium makes and releases L-DOPA during the procerss of melanin biosynthesis; L-DOPA is an endo agonist for GPR 143 (expressed at the membrane of the melanosomes) thus create an autocrine loop. GPR143 is the protein product of OA1 and mutations at this locus result in ocular albinism type 1.

Table 1 Summary of Genetic, Pathophysiologic and Clinical Features Associated with Syndromic OCA

	Hermansky-Pudlak Syndrome^Citation18	Chediak-Higashi Syndrome^Citation18	Griscelli Syndrome^Citation19	Elejalde Syndrome^Citation20	Cross-McKusick-Breen Syndrome^Citation21
Chromosome and gene involved	Chromosome 10, HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S8, BLOC1S3, BLOC1S6, AP3D1 or BLOC1S5.	Chromosome 1, CHS1/LYST	Chromosome 15: MYO5A, RAB27A Chromosome 2: MLPH	Chromosome 15: RAB27A	Chromosome 3, Gene not known
Pathophysiology	Impaired melanosome formation, trafficking, or transfer to keratinocytes	Abnormal protein trafficking	Impairment in melanosome transport	Maturation defect leading to incomplete melanosome transport and irregular distribution	Not known
Prevalence	1 to 9 in 1,000,000 individuals worldwide 1 in 1800 individuals in the north-western region of Puerto Rico (HPS1)	Rare disease, less than 500 cases have been reported so far	Rare, approximately 150 cases have been reported so far	Extremely rare, less than 25 cases have been reported so far	Extremely rare, less than 15 cases have been reported so far
Age at onset	Infancy/ Early childhood	Infancy/ Early childhood	Infancy/ Early childhood	Infancy/ Early childhood	Birth/ Early infancy
Systemic features	Immunodeficiency, Neutropenia, bleeding tendency due to platelet storage pool defect, Interstitial lung disease and/or pulmonary fibrosis, Granulomatous colitis (as per subtype)	Part of “silvery hairy syndrome” group,^Citation22 pathognomonic azurophilic granules in the white blood cells, prolonged bleeding times and easy bruisability, recurrent infections, abnormal natural killer cell function, and progressive neurological abnormalities	Part of “silvery hairy syndrome” group, combined disturbance of humoral and cell mediated immunity, hepatosplenomegaly, with or without neurological deficit	Part of “silvery hairy syndrome” group, early onset CNS disturbances like seizures, hypotony and intellectual impairment, easy tanning of skin, preserved immunological function	Early onset CNS disturbance, Dental defects, Urinary tract abnormalities, Hernias, psychomotor retardation
Major ocular features	Posterior embryotoxon with a small cluster of adherent mesenchymal cells, moderate hyalinization of the ciliary body, foveal hypoplasia, multiple ocular haemorrhages, and marked hypopigmentation^Citation23 Ocular manifestations^Citation24 in various HPS subgroups: BLOC 1- mild to moderate, BLOC 2- Severe, BLOC 3- Mild to severe, AP3- Mild	Ocular albinism with foveal hypoplasia, nystagmus, retinal pigmentary disturbances, optic neuropathy^Citation25	Ocular albinism with foveal hypoplasia, nystagmus	Ocular albinism with foveal hypoplasia, nystagmus	Ocular albinism, cataract

Abbreviations: AP-3, adaptor protein-3; BLOC, biogenesis of lysosome organelle complex; HPS, Hermansky–Pudlak syndrome.

Figure 2 Iris transillumination defect, albinotic fundus and foveal hypoplasia in pseudophakic eyes of a 41-year-old patient. Note that major retinal blood vessels show a relatively wide exit angle as they emerge from the optic disc.

Figure 3 Schematic of normal and albino visual pathways. (A) Normal visual pathways. Nerve fibres originating from temporal retina project to the ipsilateral hemisphere (red line). Nerve fibres originating from predominantly nasal retina, cross at the chiasm and project to the contralateral hemisphere (blue line). (B) Albino misrouting. The majority of optic nerve fibres decussate to the contralateral hemisphere (red and blue lines). Adapted from Neveu MM, Jeffery G. Chiasm formation in man is fundamentally different from that in the mouse. Eye. 2007;21(10):1264–1270.⁸⁶

Figure 4 Normal Flash VEPs (A) P2 peak time in ipsilateral and contralateral hemispheres of control subjects. Peak times from both hemispheres are symmetrical and shorten until approximately 18–20 years of age, do not change between 20–40 years of age, then increases beyond 40 years of age (B) P2 amplitude in ipsilateral and contralateral hemispheres of control subjects. P2 amplitudes from both hemispheres are symmetrical and reduce significantly with age (P < 0.05). Reprinted from Neveu MM, Jeffery G, Burton LC, Sloper JJ, Holder GE. Age-related changes in the dynamics of human albino visual pathways. Eur J Neurosci. 2003;18(7):1939–1949.¹¹⁰

Figure 5 Normal Pattern onset-offset VEPs (A) CII peak times in ipsilateral and contralateral hemispheres of control subjects. CII peak times from both hemispheres are symmetrical and significantly shorten with increasing age (P < 0.0001). (B) CII amplitude in ipsilateral and contralateral hemispheres of control subjects. CII amplitudes from both hemispheres are symmetrical. P2 amplitude reduces significantly with age (P < 0.005). Reprinted from Neveu MM, Jeffery G, Burton LC, Sloper JJ, Holder GE. Age-related changes in the dynamics of human albino visual pathways. Eur J Neurosci. 2003;18(7):1939–1949.¹¹⁰

Figure 6 Pattern onset-offset VEPs and Flash VEPs from an age-matched control (A) and a 60 year old patient with albinism (B, C) using five scalp electrodes positioned over the occiput; 2 electrodes over the right hemisphere; two electrodes over the left hemisphere; 1 electrode over the midline. (A) VEP responses from control subject are symmetrical and of similar amplitude and peak time from the left and right hemisphere. (B). Pattern onset-offset VEP responses from a 60-year-old patient with albinism. Right eye (rows 2) VEP responses are of shorter peak and/or larger amplitude from the left hemisphere compared with the right hemisphere. Left eye (rows 3) VEP responses are of shorter peak and/or larger amplitude from the right hemisphere compared with the left hemisphere. (C) Flash VEP responses from a 60-year-old patient with albinism. VEP responses from both eyes are symmetrical and of similar amplitude and peak time from the left and right hemisphere.

Figure 7 Flash VEPs from an 8-month-old patient with albinism using five occipital scalp electrodes; 2 electrodes over the right hemisphere; 2 electrodes over the left hemisphere; 1 electrode over the midline. Right eye (row 1) VEP responses are of higher amplitude from the left hemisphere compared with the right hemisphere. Left eye (row 2) VEP responses are of higher amplitude from the right hemisphere compared with the left hemisphere.

Figure 8 Flash VEP characteristics in 83 patients with albinism including 17 genetically confirmed cases of OCA, 3 cases of OA, 5 cases of HP syndrome and 1 case of CH Syndrome. (A) P2 amplitude in ipsilateral (bold line) and contralateral (dashed line) hemispheres. There is a significant inter-hemispheric amplitude difference up until ~18 years of age. There is no significant inter-hemispheric difference beyond 18 years. (B) Flash VEP P2 peak time in ipsilateral (bold line) and contralateral (dashed line) hemispheres of patients with albinism. P2 peak times in both hemispheres are symmetrical and similar to those in control subjects. Black filled data points are from genetically confirmed patients. Data from Neveu MM, Jeffery G, Burton LC, Sloper JJ, Holder GE. Age-related changes in the dynamics of human albino visual pathways. Eur J Neurosci. 2003;18(7):1939-1949¹¹⁰, with additional patients and highlighting of genetically confirmed cases.

Figure 9 Pattern onset-offset VEP characteristics in 66 patients with albinism including 8 genetically confirmed cases of OCA, 3 cases of OA, 2 cases of HP syndrome and 1 case of CH Syndrome. (A) CII peak time in ipsilateral (bold line) and contralateral hemispheres (dashed line). CII peak time in the contralateral hemisphere is shorter than peak time in the ipsilateral hemisphere for all ages. The inter-hemispheric peak time difference increases with age. (B) CII amplitude in ipsilateral (bold line) and contralateral (dashed line) hemispheres of patient with albinism. CII amplitudes in both hemispheres are symmetrical, similar to that in control subjects. Black filled data points are from genetically confirmed patients. Data from Neveu MM, Jeffery G, Burton LC, Sloper JJ, Holder GE. Age-related changes in the dynamics of human albino visual pathways. Eur J Neurosci. 2003 Oct;18(7):1939-1949¹¹⁰, with additional patients and highlighting of genetically confirmed cases.

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