Albinism – symptomatology, aetiology, and therapy

INTRODUCTION

Albinism (from the Latin “albus”, meaning “white”) is a rare, genetically determined disorder of the melanogenesis resulting in a reduction or complete absence of melanin in tissues of ectodermal origin, especially skin, hair, and irises of the eyes [1]. Melanin is a biopolymer produced in brown-black (eumelanin) and red-yellow (pheomelanin). Biosynthesis of both eumelanin and pheomelanin begins the same way. Tyrosine is converted into dihydroxyphenylalanine (DOPA), which requires tyrosine hydroxylase and tetrahydrobiopterin as a cofactor. The enzyme tyrosinase then converts DOPA into dopaquinone, which can form the eumelanin or pheomelanin. Eumelanin, rich in nitrogen, plays a role in protecting the skin against damage caused by ultraviolet radiation. Complete lack of eumelanin production deprives of natural protection against UV, which results in an increased risk of skin diseases. Pheomelanin, however, is rich in sulphur and does not have photoprotective properties. Although it does not have a protective function against external factors, it gives minimal colour [2]. Melanogenesis in lighter forms of albinism is directed at the production of pheomelanin. The phenotypic variability of albinism is wide and ranges from complete absence of pigmentation of the hair, skin, and/or irises to mild depigmentation. In more severe forms of albinism, the melanogenesis process is blocked.

CLASSIFICATION

There are 2 main groups of albinism: syndromic and isolated (with its 2 forms, oculocutaneous albinism – OCA, and ocular albinism – OA). In OCA features such as colour/degree of hypopigmentation of the skin, hair, and/or irises of the eyes coexist with ocular abnormalities/vision disorders, while OA primarily affects the eyes. Oculocutaneous albinism is inherited in an autosomal recessive manner, while OA is typically inherited in an X-linked recessive manner. Oculocutaneous albinism may take on 8 different types (OCA1-8). All are caused by a pathogenic variant in one of the genes involved in the melanin biosynthesis process, with the exception of OCA5 associated with the chromosomal region 4q24 with no causative gene identified so far [1, 3–6]. Moreover, OCA type 1 albinism is divided into subtypes OCA1A and OCA1B – both caused by molecular variants in TYR gene encoding tyrosinase [7, 8]. Isolated forms of albinism with its genetic background and clinical characteristics are presented in Table 1. Oculocutaneous albinism and/or hypopigmentation of skin/hair/irises may be one of the clinical manifestations in some complex syndromes with involvement of various systems, in which concomitant hearing loss, peripheral neuropathy, immunodeficiency, cardiomyopathy, brain defects, platelet dysfunction, or dysmorphia in various constellations may occur. Table 2 presents selected syndromes with albinism, divided into types according to genetic background.

EPIDEMIOLOGY

The worldwide prevalence of albinism is estimated at 1 : 17,000 to 1 : 20,000 [1, 9]. The most common form of isolated albinism (1 : 39,000) is OCA2 with a prevalence in African Americans of 1 : 10,000), in all Americans at 36,000, and in Sub-Saharan Africans at 1 : 3900 [10]. OCA1, with a prevalence of 1 : 40,000, occurs the most frequently among Europeans, and it is one of the most common forms of OCA in America and China, accounting for 70% of cases [3]. OCA3 with an overall prevalence of 1 : 8500, occurs mainly in southern Africa [10, 11]. The prevalence of OCA4 is 1 : 100,000, but it accounts for 24% of OCA in the Japanese population [12, 13]. The very rare OCA5 has been described in a Pakistani family [5], while OCA6 was reported in single Chinese and East Indian families. The overall prevalence of OA is estimated at 1 : 60,000 [14]. According to Orphanet, the prevalence of selected syndromes associated with albinism is as follows: Hermansky-Pudlak 1–9 : 1,000,000, Waardenburg 1 : 40,000, Tietz, Griscelli, and Vici < 1 : 1,000,000. Only 500 cases with Chediak-Higasi have been described so far.

AETIOLOGY AND GENETIC BACKGROUND

Pigmentation genes in humans (approximately 120) as a result of regulatory processes control the number and size of melanosomes, as well as the amount and type of melanin synthesised and its distribution. The TYR gene encodes tyrosinase, which plays a key role in the melanin biosynthesis process. Mutations of the TYR gene (TYR), which cause OCA1, may cause complete or partial inactivation of tyrosinase, leading to the most severe or the milder form of albinism, where in the latter form biosynthesis of the yellow-red pheomelanin predominates [7, 8, 15, 16]. The OCA2 gene, responsible for OCA2, encodes the melanosome transmembrane protein P. Its exact functions are not fully understood, but it appears to be involved in transporting proteins into melanosomes, stabilising the melanosomal protein complex, and regulating pH within the melanosome, which are crucial in the process of melanin biosynthesis [17]. The TYPR1 gene (OCA3) encodes a protein related to tyrosinase, which stabilises and modulates its activity, supporting the process of melanin biosynthesis and contributing to maintaining the integrity of the melanosome [18, 19]. The product of SLC45A2 (OCA4) is a melanosomal membrane transporter protein that transports substances needed for melanin biosynthesis to the melanosome [12]. The SLC24A5 (OCA5) gene encodes protein that is important for the maturation and architecture of melanosomes [20], and LRMDA (c10orf11) (OCA7) ­– for melanocyte differentiation, regulating early stages of melanosome biogenesis [21]. Tyrosinase-related protein 2 encoded by the DCT gene (OCA8) is one of the 3 key enzymes in the biosynthesis of eumelanin [22, 23]. And finally, the GPR143 gene encodes an intracellular G-protein-coupled receptor involved in melanosome biogenesis and is responsible for OA [24].

CLINICAL CHARACTERISTICS

Skin manifestations of OCA include hypopigmentation, which may vary individually and is subject to change with age. Consequences of skin exposure to sunlight may help to assess the severity of hypopigmentation – the greater the degree of depigmentation, the higher risk of skin burning instead of tanning [1, 3–5]. Due to the reduction or lack of eumelanin, individuals with albinism have an increased risk of sun damage to the skin: lentigines, actinic keratosis, solar erythema, as well as an increased risk of skin cancer, e.g. squamous cell, basal cell carcinoma, or melanoma. The first is the most common malignant tumour found in people with albinism (over 75% of cases), developing already in teenage years. Basal cell carcinoma accounts for approximately 24%, and melanoma – only 1% of all skin cancers in patients with albinism [5, 25]. An impaired process of melanin biosynthesis may cause various eye abnormalities. The most common include the following: early-onset nystagmus mainly in the horizontal plane, seen in the first weeks of life, refractive errors, including hypermetropia/myopia and astigmatism, strabismus, and decreased visual acuity. Loss of retinal pigment epithelium with transillumination, observed in the majority of patients with albinism, is associated with photophobia. On fundus examination, reduced pigmentation retinal epithelium and choroid, foveal hypoplasia and optic nerve abnormalities are present. Chiasmal misrouting was also reported [1, 3–5].
Psychological issues may be associated both with visual impairment and with general appearance, because albinism is a disease with characteristic presentation, which is easy to notice. Visual problems may influence early neurodevelopment in many aspects, i.e. acquisition of motor skills, hand-eye coordination, language and communication, social abilities, and cognition; however, some improvement in school performance is seen with age, and problems in reading are observed only in some patients with OCA/OA. Anxiety and depressive disorders are much more frequent in this group in comparison to the general paediatric population, and more than half of OCA/OA patients present at least one feature characteristic of autism spectrum disorders or attention deficit hyperactivity disorder (ADHD) [26, 27]. A significant problem for people suffering from albinism is their unusual appearance, which arouses interest in others or causes ridicule and lack of social acceptance. In some cultures, the fate of people with albinism is particularly dramatic. They are subject to harassment, persecution, and even murder due to the prevailing superstition that their body parts have magical powers and ensure the success of their purchasers [28].
More detailed clinical characteristics of various forms of isolated OCA and OA are presented in Table 1, while a clinical description of syndromes associated with albinism is presented in Table 2.

DIAGNOSIS

Clinical findings may not accurately predict a molecular diagnosis, and the spectrum of clinical disease varies widely as many patients with OCA are compound heterozygotes. The diagnostic yield of whole-genome sequencing or targeted gene panels for albinism with positive yields ranges 28–91%. The presence or absence of cutaneous involvement of albinism significantly affects genetic diagnostic yield. The overall initial genetic diagnostic yield of OA/OCA in the paediatric population is 66% [39–41]. There is no significant difference between race and ethnicities; however, the diagnostic yield of OA (33%) is significantly lower (p = 0.007) than OCA (76%). Causative variants in OCA2 (28%) and TYR (20%) are most common [39]. Among missense variants in the TYR gene, which are predominant, there are pathogenic mutations and functional polymorphisms – the most common are c.575A > C, p.Tyr92Ser and c.1205G > A, p.Arg402Gln [42–45]. Furthermore, Hermansky-Pudlak syndrome variants were identified in 9% of patients [39]. Re-classification of variants of uncertain significance (VUS) in non-diagnostic cases resulted in genetic diagnoses for 29% of individuals and increased the overall diagnostic yield to 70% of all subjects [39, 40].

TREATMENT

Albinism is an incurable disorder. It is only possible to prevent its negative effects and treat complications caused by the lack of melanin. Albinism significantly limits the normal existence of people affected by it – permanent protection of the body against solar radiation is required. In patients with visual acuity reduction some daily activities like reading, writing, and working with a computer may be difficult, which in turn has a major impact on the professional life of these people. To provide eye protection using special filtering glasses is recommended. To improve visual acuity appropriate correction of refractive errors is helpful, and where appropriate, surgical correction of abnormal head posture in selected cases of nystagmus [46, 47]. Novel strategies for systemic treatment of subtypes of albinism are in preclinical testing. Currently, novel therapies that aim to directly address the molecular errors of albinism, such as l-DOPA and nitisinone [48], are being developed and have entered human trials though with limited success. Experimental gene-based strategies for editing the genetic errors in albinism have also met early success in animal models [49]. The emergence of these new therapeutic modalities represents a new era in the management of albinism [46].

DISCLOSURES

1. This work was supported by Children’s Memorial Health Institute grant No. M48/20.
2. Assistance with the article: None.
3. Financial support and sponsorship: None.
4. Conflicts of interest: None.

References