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- Albinism: for patients
|Genes involved (OMIM No.)||18 genes have been identified to cause syndromic and non-syndromic oculocutaneous albinism (OCA), with the most common being:|
|Molecular diagnosis||Next generation sequencing|
|Therapies under research|
Albinism is an inherited pigmentary disorder caused by pathogenic mutations leading to reduced melanin production or dysfunctional melanin transport within melanocyte-containing cells. It can manifest either as syndromic/non-syndromic oculocutaneous albinism (OCA), where the eyes, skin and hair are affected or ocular albinism (OA), where there is isolated ocular pathology.
Children usually present with infantile nystagmus syndrome (involuntary and predominantly horizontal conjugate oscillations of the eyes that develops at birth or shortly afterwards and persists throughout life) with reduced visual acuity (VA). Some children may present with an anomalous head posture instead due to utilisation of a null point (an area of minimum nystagmus and better vision) to optimise visual acuity. Cutaneous changes can also be observed in those affected by OCA but to varying degrees.
The severities of the ocular and cutaneous phenotypes show significant intra- and inter-familial variability depending on the causative gene and the degree of melanin deficiency. For example, OCA1A patients, who have complete lack of tyrosinase activity due to TYR mutations will express the classic phenotype of pale white skin, blonde hair and complete iris transillumination. VA usually ranges from 6/30 to 6/120 (LogMAR 0.7-1.3). On the other hand, those with OCA2 mutations have mild to moderate degree of pigmentation with slightly better VA, usually ranging from 6/19 to 6/30 (LogMAR 0.5-0.7). Skin pigmentation may increase with time such as in patients with some residual tyrosinase activity (OCA1B). Initially, they are identical to OCA1A patients but usually show some melanisation of skin (cream to tan colour with light naevi and freckles) and hair (ranging from yellow to light brown) by the age of three years.
Apart from infantile nystagmus, a range of other ocular features are associated with OA and OCA:
- Refractive error
- Iris hypopigmentation and iris transillumination
- Fundal hypopigmentation (due to retinal pigment epithelium [RPE] depigmentation)
- Foveal hypoplasia
- Chiasmal misrouting (can be detected on visual evoked potential [VEP] testing)
Variable reduction in pigmentation of the iris and RPE result in a spectrum of clinical severity. The iris may range from severe hypopigmentation resulting in diffuse iris transillumination that is visible without slit lamp examination to heavy pigmentation with no obvious transillumination. The fundus may appear normally pigmented or blonde at the most severe end of the spectrum. Foveal morphology may also vary among patients, ranging from normal to plana which has been shown to correlate with VA. Importantly, visual function does not tend to deteriorate over time.
Associated extraocular features
Apart from skin and hair depigmentation, OCA may be associated with other extraocular features forming a syndrome. Typical examples include:
- Hermansky-Pudlak syndrome—an autosomal recessive disorder associated with pathogenic mutations in 10 genes. It is characterised by bleeding diathesis (easy/prolonged bleeding, easy bruising, prolonged/heavy menorrhagia, epistaxis), and in some individuals accompanied with later-onset pulmonary fibrosis (onset usually during early 30s), granulomatous colitis and immunodeficiency
- Chediak-Higashi syndrome—an autosomal recessive disorder caused by pathogenic mutations in the LYST gene. It is characterised by easy bruising and early onset recurrent infections with or without neurological symptoms such as ataxia and weakness. Most patients to do not survive past the first decade of life, and if untreated, a life-threatening medical emergency called the accelerated phase can occur at any point. It is marked by fever, hepatosplenomegaly, lymphadenopathy and pan-cytopenia
Genes associated with Hermansky-Pudlak syndrome (with associated OMIM no.)
Certain genotype-phenotype relationship can be observed[4,5]:
- Pulmonary fibrosis— commonly associated with HPS1, AP3B1, HPS4 variants
- Granulomatous colitis— commonly associated with HPS1 and HPS4 variants
- Immunodeficiency— commonly associated with AP3B1 and AP3D1 variants
Pathogenic mutations in 18 genes have been identified to cause OCA (syndromic/non-syndromic) or OA by affecting melanin biosynthesis or melanin distribution in dermal tissues.
The prevalence of each causative gene depends on the population studied[2,6]:
- TYR (most common among Caucasians)
- OCA2 (most common worldwide; high prevalence in sub-Saharan Africa)
- TYRP1 (rare among Caucasians but affects 1:8,500 African individuals in Southern Africa)
- OCA4 (rare among Caucasians and Africans but accounts for 25% of OCA cases in Japan)
- GPR143 (the only gene associated with the OA phenotype)
Melanin is synthesised from an organelle called melanosomes which are located inside melanocytes. Melanocytes are derived from the neural crest ectoderm during embryonic development and migrate into the skin, hair, eyes and inner ear to fulfil their primary function. Melanogenesis is tightly regulated by the activity of tyrosinase. It converts L-tyrosine to L-DOPA or dopaquinone for the production of eumelanin (brown to black colour) or pheomelanin (red to yellow colour), two common forms of melanin in humans. Mature melanosomes are transferred to the surrounding cells through the dendrites of melanocytes.
Apart from its role in protecting the skin from harmful ultraviolet (UV) rays, melanin is also crucial to the development of ocular structures and neural pathways. It induces the formation of fovea, optic nerves, optic tracts and visual cortex, along with triggering the crossover of optic nerve fibres from each eye at the chiasm to the contralateral occipital lobe, which is essential for binocular vision.
|Melanosome maturation and melanin biosynthesis||TYR, OCA2, TYRP1, SLC45A2, SLC24A5, LRMDA, GPR143, HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, BLOC1S6|
|Biogenesis of platelet dense granules and/or lysosomes||HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, BLOC1S6|
|Regulation of lysosomal trafficking||LYST, AP3D1|
1) Orthoptic assessment and refraction
To assess current level of vision and determine if amblyopia therapy and/or refractive correction are required to optimise vision.
2) Optical coherence tomography (OCT)
OCT can detect the presence of foveal hypoplasia to support the clinical diagnosis and document its severity.
Visual evoked potentials can be requested to look for evidence of chiasmal misrouting.
4) Eye movement recordings
Eye movement recordings can help differentiate between infantile nystagmus syndrome (INS) with a latent component and Fusion Maldevelopment Nystagmus syndrome (or latent nystagmus). Both are conjugate, horizontal nystagmus but INS has a pathognomonic waveform with an accelerating exponential slow phase.
5) Dilated fundal examination of family members
This can be especially helpful in determining whether an affected male child in lighter-skinned families has X-linked OA (if family history is not obvious) as female carriers tend to have irregular fundal pigmentation due to X-lyonisation.
Due to the variability of skin depigmentation, comparing the skin colour of the patient with other family members may help in diagnosing OCA, especially if the patient has residual pigmentation and the ocular manifestations are mild.
Referral to a paediatrician and other relevant specialists should be made for patients with features suggestive of Hermansky-Pudlak syndrome (easy bleeding/bruising) or Chediak-Higashi syndrome (recurrent infections), or guided by the results of genetic testing.
Diagnosis of OCA or OA is usually made clinically. Genetic testing should be undertaken to obtain a molecular diagnosis which can help in directing further clinical management, facilitating genetic counselling and providing accurate advice on prognosis and future family planning.
This can be achieved through a variety of next generation sequencing (NGS) methods:
- Targeted gene panels (albinism)
- Whole exome sequencing
- Whole genome sequencing
Detection and prompt management of amblyopia is the most important ocular management in albinism. Correction of refractive errors with either glasses/contact lenses should be prescribed as early as possible. Amblyopia can be managed as standard (occlusion and/or atropine drops) if there is no latent component, or with prolonged occlusion if there is confirmed visual improvement and dampening of nystagmus on eye movement recordings. Photochromic or tinted glasses can be beneficial for patients experiencing photophobia.
Medical treatments with oral gabapentin or memantine have been shown to improve VA by reducing nystagmus intensity[12,13] , with a larger treatment effect observed in patients with infantile idiopathic nystagmus compared to those with a secondary cause in a randomised placebo-controlled trial. Evidence in children is lacking however.
If a significant head posture/head turn is adopted to utilise the null point, surgical management may be considered. The aim of surgery is to shift the null point centrally (i.e. towards the direction of the head turn) and therefore reduces the extent of head turn. This can be achieved through various methods[15-18] but the Anderson-Kestenbaum approach (recession of the horizontal recti at the direction of the head turn and resection of the corresponding horizontal recti) remains standard in the UK.
Visual impairment can have a negative impact on a child’s early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.
The Developmental Journal for babies and young children with visual impairment (DJVI) is a structured early intervention programme designed to track developmental and vision progress from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents.
Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.
Due to the increased risk of skin malignancy, patients should be advised of the following:
- Adequate skin protection from sun exposure such as using sun block, long sleeved clothing and wearing caps or hats with a wide brim
- Annual examination to look for basal or squamous cell carcinomas
A multidisciplinary approach involving haematologists is required for patients affected by Hermansky-Pudlak (HPS) and Chediak-Higashi (CH) syndromes. An urgent referral should be made for those suspicious of CH so that detailed assessment and treatment can be initiated as soon as possible, preferably before the development of the accelerated phase. Haematological and immune deficiency associated with CH are treated with haematopoetic stem cell transplant.
For HPS patients, a referral to the respiratory physician or gastroenterologist may be required depending on the genetic subtype. For those at higher risk of developing pulmonary fibrosis (HPS1, AP3B1, HPS4), an annual CT chest with high resolution images are advised along with pulmonary function tests.
|Gene||Pulmonary Fibrosis||Colitis||Immune Deficiency|
|HPS1||High Risk||High Risk||Low Risk|
|AP3B1 (HPS2)||High Risk||Low Risk||High Risk|
|HPS4||High Risk||High Risk||Low Risk|
|AP3D1||Low Risk||Low Risk||High Risk|
Family management and counselling
Emotional and social support
Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients in clinic. They provide emotional and practical support to help patients deal with their diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.
Referral to a specialist centre
In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.
Nitisinone is an FDA-approved drug used for the treatment of type 1 tyrosinemia, a condition caused by deficient fumarylacetoacetate hydrolase (FAH) activity leading to failure of tyrosine degradation. It is characterised by progressive liver disease and secondary renal tubular dysfunction. Nitisinone inhibits an enzyme upstream in the tyrosinase catabolism pathway, thereby preventing the accumulation of toxic metabolites of FAH deficiency. As a result of its mechanism, an increase in plasma tyrosine concentration can be observed in treated patients.
Pre-clinical experiments on a mouse model of OCA1B showed that oral nitisinone resulted in increased fur and iris pigmentation, possibly due to stabilisation of mutant tyrosinase protein with saturating tyrosine levels. This translated into a phase 1/2 pilot study where 5 adult patients were treated with a fixed, daily low dose oral nitisinone for 1 year. Although there was no significant change in iris transillumination (primary outcome), an increase in hair and skin pigmentation were observed. Patients also experienced a statistically but not clinically significant improvement in BCVA.
Despite pre-clinical evidence[22,23] suggesting that levodopa supplementation may improve retinal development and therefore visual function, OCA patients enrolled in a phase 1/2 trial did not show a statistically significant improvement in BCVA.
- Research Opportunities at Moorfields Eye Hospital UK
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- Thomas MG, Maconachie G, Hisaund M, Gottlob I. FRMD7-Related Infantile Nystagmus. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993
- Federico JR, Krishnamurthy K. Albinism. In: StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2020, StatPearls Publishing LLC.; 2020
- Thomas MG, Kumar A, Mohammad S, et al. Structural grading of foveal hypoplasia using spectral-domain optical coherence tomography a predictor of visual acuity? Ophthalmology. 2011;118(8):1653-1660
- Brantly M, Avila NA, Shotelersuk V, Lucero C, Huizing M, Gahl WA. Pulmonary function and high-resolution CT findings in patients with an inherited form of pulmonary fibrosis, Hermansky-Pudlak syndrome, due to mutations in HPS-1. Chest. 2000;117(1):129-136
- Huizing M, Anikster Y, Gahl WA. Hermansky-Pudlak syndrome and related disorders of organelle formation. Traffic. 2000;1(11):823-835
- Kamaraj B, Purohit R. Mutational analysis of oculocutaneous albinism: a compact review. Biomed Res Int. 2014;2014:905472
- Maranduca MA, Branisteanu D, Serban DN, et al. Synthesis and physiological implications of melanic pigments. Oncol Lett. 2019;17(5):4183-4187
- Delevoye C. Melanin transfer: the keratinocytes are more than gluttons. J Invest Dermatol. 2014;134(4):877-879
- Dell’Osso LF, Daroff RB. Congenital nystagmus waveforms and foveation strategy. Doc Ophthalmol. 1975;39(1):155-182
- Lewis RA. Ocular Albinism, X-Linked. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993
- Simonsz HJ, Kommerell G. The effect of prolonged monocular occlusion on latent nystagmus in the treatment of amblyopia. Bull Soc Belge Ophtalmol. 1989;232:7-12
- Shery T, Proudlock FA, Sarvananthan N, McLean RJ, Gottlob I. The effects of gabapentin and memantine in acquired and congenital nystagmus: a retrospective study. Br J Ophthalmol. 2006;90(7):839-843
- Sarvananthan N, Proudlock FA, Choudhuri I, Dua H, Gottlob I. Pharmacologic Treatment of Congenital Nystagmus. Archives of Ophthalmology. 2006;124(6):916-918
- McLean R, Proudlock F, Thomas S, Degg C, Gottlob I. Congenital nystagmus: randomized, controlled, double-masked trial of memantine/gabapentin. Ann Neurol. 2007;61(2):130-138
- Hertle RW, Dell’Osso LF, FitzGibbon EJ, Thompson D, Yang D, Mellow SD. Horizontal rectus tenotomy in patients with congenital nystagmus: results in 10 adults. Ophthalmology. 2003;110(11):2097-2105
- Hertle RW, Dell’Osso LF, FitzGibbon EJ, Yang D, Mellow SD. Horizontal rectus muscle tenotomy in children with infantile nystagmus syndrome: a pilot study. J aapos. 2004;8(6):539-548
- Lingua RW, Liu CY, Gerling A, Zhang Z, Nalbandian A. Myectomy of the Extraocular Muscles Without Reattachment as a Surgical Treatment for Horizontal Nystagmus. J Pediatr Ophthalmol Strabismus. 2016;53(3):156-166
- Lingua RW, Liu CY, Gerling A, Zhang Z, Nalbandian A. Further Considerations in the Management of Nystagmus with Myectomy. J Pediatr Ophthalmol Strabismus. 2016;53(4):255
- Lozano ML, Rivera J, Sánchez-Guiu I, Vicente V. Towards the targeted management of Chediak-Higashi syndrome. Orphanet Journal of Rare Diseases. 2014;9(1):132
- Das AM. Clinical utility of nitisinone for the treatment of hereditary tyrosinemia type-1 (HT-1). Appl Clin Genet. 2017;10:43-48
- Onojafe IF, Adams DR, Simeonov DR, et al. Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism. J Clin Invest. 2011;121(10):3914-3923
- Roffler-Tarlov S, Liu JH, Naumova EN, Bernal-Ayala MM, Mason CA. L-Dopa and the albino riddle: content of L-Dopa in the developing retina of pigmented and albino mice. PLoS One. 2013;8(3):e57184
- Summers CG, Connett JE, Holleschau AM, et al. Does levodopa improve vision in albinism? Results of a randomized, controlled clinical trial. Clin Exp Ophthalmol. 2014;42(8):713-721