Albinism: for professionals

• Overview
• Clinical phenotype
• Genetics
• Key investigations
• Diagnosis
• Management
• Current research
• Further information and support
• References
• Albinism: for patients

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Overview

Prevalence	1-5,000 to 17,000
Inheritance	Autosomal recessive X-linked
Genes involved (OMIM No.)	18 genes have been identified to cause syndromic and non-syndromic oculocutaneous albinism (OCA), with the most common being: TYR (#606933) — Most common among Caucasians OCA2 (#611409) — Most common worldwide TYRP1 (#115501) — Primarily in southern African populations; rare among Caucasians Ocular albinism (OA) is due to pathogenic mutations in the GPR143 gene (#300808)
Symptoms	Photophobia Poor vision
Signs	Infantile nystagmus Reduced visual acuity Strabismus Iris transillumination Fundal hypopigmentation Foveal hypoplasia Intra- and interfamilial variability in disease severity
Systemic features	Skin and hair depigmentation in oculocutaneous albinism (OCA) OCA may be syndromic, such as Hermansky-Pudlak syndrome (mainly bleeding diathesis with pulmonary fibrosis, granulomatous colitis and/or immunodeficiency in some) and Chediak-Higashi syndrome (early onset recurrent infections, easy bruising +/- neurological symptoms)
Key investigations	Orthoptic assessment and refraction VEP: Evidence of intracranial chiasmal misrouting OCT: To detect foveal hypoplasia Eye movement recording Assessment/screening by other specialists may be required if features suggestive of wider systemic involvement are present or based on genetic result
Molecular diagnosis	Next generation sequencing Targeted gene panels (albinism) Whole exome sequencing Whole genome sequencing
Management	Ocular Amblyopia management Correction of refractive errors Surgical management may be required to address significant abnormal head positions adopted to optimise vision at a null point Photochromic/tinted glasses Systemic Multidisciplinary approach Early referral to practitioners familiar with developmental surveillance and intervention in young children with visual impairment to optimise development Appropriate skin protection from sun exposure Annual skin examination to look for signs of skin malignancies
Therapies under research	Oral nitisinone has been shown to increase skin and hair pigmentation in a pilot study

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Clinical phenotype

Presenting features

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.^[1] 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).^[2] 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).^[2] 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.

Ocular features

Apart from infantile nystagmus, a range of other ocular features are associated with OA and OCA:

• Strabismus
• Photophobia
• 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.^[3] 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.)

HPS1 (#604982), AP3B1 (#603401), HPS3 (#606118), HPS4 (#606682), HPS5 (#607521), HPS6 (#607522), DTNBP1 (#607145), BLOC1S3 (#609762), AP3D1 (#607246)

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

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Genetics

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.^[2] 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.^[7] Mature melanosomes are transferred to the surrounding cells through the dendrites of melanocytes.^[8]

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.^[2]

General Function	Genes
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

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

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.^[3]

3) Electrophysiology

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.^[9]

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.^[10]

Systemic

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.

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Diagnosis

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

Related links

• Genomics England PanelApp for albinism
• Genetic counselling: for professionals

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Management

Ocular

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^[11] 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.^[14] 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.

Development

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.

Systemic

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.^[19]

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

Syndromic and non-syndromic OCA are inherited in an autosomal recessive manner while OA is inherited in an X-linked manner.

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

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.

Related links

• Coping with sight loss
• Education and learning
• Family support service

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.

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Current research in albinism

1) Nitisinone

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.^[20] 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.^[21] 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.

2) Levodopa

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.^[23]

Related links

• Research Opportunities at Moorfields Eye Hospital UK
• Searching for current clinical research or trials

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Further information and support

• Nystagmus Network
• Albinism Fellowship
• Royal National Institute of Blind People (RNIB)
• Look UK
• VICTA

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References

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