Current and Emerging Treatments for Albinism
Siyin Liu, MRes, Helen J. Kuht, BMedSci, Emily Haejoon Moon, MBChB, Gail DE. Maconachie, PhD, Mervyn G. Thomas, PhD
PII: S0039-6257(20)30145-4
DOI: https://doi.org/10.1016/j.survophthal.2020.10.007 Reference: SOP 6980
To appear in: Survey of Ophthalmology
Received Date: 3 May 2020
Revised Date: 7 October 2020
Accepted Date: 21 October 2020
Please cite this article as: Liu S, Kuht HJ, Moon EH, Maconachie GD, Thomas MG, Current and Emerging Treatments for Albinism, Survey of Ophthalmology (2020), doi: https://doi.org/10.1016/ j.survophthal.2020.10.007.
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Title: Current and Emerging Treatments for Albinism
Authors: Siyin Liu MResa,b, Helen J Kuht BMedScia, Emily Haejoon Moon MBChBc, Gail DE Maconachie PhDa,d*, Mervyn G Thomas PhDa*
Affiliations:
aThe University of Leicester Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behaviour, University of Leicester, RKCSB, PO Box 65, Leicester LE2 7LX, UK bManchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester,
United Kingdom
cAddenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust,
Cambridge, United Kingdom
dHealth Sciences School, Division of Ophthalmology & Orthoptics, University of Sheffield, United Kingdom
*These authors contributed equally.
Corresponding authors, Tel: +44 (0)116 252 5879, Fax: +44 (0)116 223 1996, email: [email protected] and [email protected]
Financial Support: This work was supported by Fight for Sight (grant ref: 5009/5010 and 24NN181), Ulverscroft Foundation, Academy of Medical Sciences and the Medical Research Council (MRC), London, UK (grant number: MC_PC_17171). MGT is supported by the NIHR (CL-2017-11-003).
The sponsor or funding organization had no role in the design or conduct of this work
Abstract
Albinism is a group of rare inherited disorders arising from impairment of melanin biosynthesis. The reduction of melanin synthesis leads to hypopigmentation of skin and eyes. A wide range of ophthalmic manifestations arise from albinism, including reduction of visual acuity, nystagmus, strabismus, iris translucency, foveal hypoplasia, fundus hypopigmentation, and abnormal decussation of retinal ganglion cell axons at the optic chiasm. Currently, albinism is incurable, and treatment aims either surgically or pharmacologically to optimize vision and protect skin; however, novel therapies that aim to directly address the molecular errors of albinism, such as L-dihydroxyphenylalanine (L-DOPA) and nitisinone, 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. The emergence of these new therapeutic modalities represents a new era in
the management of albinism. We focus on the known genetic subtypes, clinical assessment, existing and emerging therapeutic options for the non-syndromic forms of albinism.
Key Words
albinism, OCA, OA, nystagmus, abnormal head posture, glare, skin protection, L-DOPA, nitisinone, gene therapy
I. Introduction
Albinism is a group of rare inherited disorders arising from impairment of melanin biosynthesis56. Melanin production is closely regulated and takes place in melanocytes, which are specialized ectodermal-derived cells originating from either a cutaneous (skin, hair) or extracutaneous (eye) lineage. In oculocutaneous albinism (OCA) abnormal melanin production leads to hypopigmentation in skin, hair and eyes with characteristic ocular abnormalities; whereas in ocular albinism (OA) only the visual pathway is affected.
Disabling ophthalmic manifestions in patients with albinism include non-progressive reduction of visual acuity (VA), nystagmus, strabismus, iris translucency, foveal hypoplasia, fundus hypopigmentation, and abnormal decussation of retinal ganglion cell axons at the optic chiasm56,110.
Albinism is genetically heterogenous and is categorized into different subtypes based on the gene involved118,141. Mutations in 6 genes cause non-syndromic OCA, including TYR, OCA2, TYRP1, SLC45A2, SLC24A5, LRMDA, corresponding to OCA1, 2, 3, 4, 6, and 7 respectively; whereas OA1 is caused by mutations of the X-linked GPR143 (OA1) gene118. OCA5 was linked to a mutation on chromosome 4q24, but the exact gene affected has not yet been identified81. Syndromic form of albinism has the phenotypic characteristics of OCA but with additional pathological features, this include Hermansky-Pudlak Syndrome (HPS), Waardenburg Syndrome(WS), Chediak-Higashi Syndrome (CHS), Griscelli Syndrome (GS)118, and a newly discovered lysosomal disorder caused by mutation of CLCN7122.
All ethnicities can be affected by albinism. In Western countries, the prevalence of albinism has been reported to be between 1:14000 to 1:1700057,110,171; whereas in Africa it is estimated to be 1:5000 to 1:1500069. Prevalence of individual subtypes varies considerably among different populations. OCA1 is rare in African-Americans56; African patients are more prone to be affected by OCA286. OCA3 is seldomly found in Caucasian and Asiatic populations, but affects 1:8500 individuals in Africa78,142, whereas OCA4 is the most common subtype of albinism in Japan and is diagnosed in 1 in 4 patient with OCA71,141.
Treatment focuses on improving the quality of life of individuals with albinism, such as correcting refractive errors and eye muscle surgeries that may benefit patients with strabismus or nystagmus90,96,167. There is currently, however, no cure for albinism. With the
aim of directly addressing the fundamental molecular errors in albinism, innovative therapies in animal models include the use of nitisinone, L‐dihydroxyphenylalanine (L‐DOPA), aminoglycosidesA, chemical chaperone therapy, and gene therapy49,94,132,154,158,160.
Here we provide a comprehensive review of the known genetic subtypes, clinical assessment, existing and emerging therapeutic options for the non-syndromic forms of albinism, with attention to ophthalmic manifestations.
II. Melanin Biosynthesis
Pigmentation of our hair, skin and eyes are primarily determined by a group of natural pigments called “melanin”. In humans there are two main subtypes of melanin: the black- brown eumelanin and the red-yellow pheomelanin. The color of skin, hair and eye is determined by the total quantity of melanin present and the ratio of its subtypes72,168.
Melanin is produced within cells called melanocytes that have different embryonic origins depending on their populating location. For instance, epidermal melanocytes in the uveal tract of the eye, hair, and the interfollicular epidermis of skin are derived from neural crest cells18,153. On the other hand, melanocytes in iris/ciliary epithelium and retinal pigmented epithelium (RPE) originate embryologically from the neuroectoderm of the primitive forebrain19,146.
Within melanocytes, melanin is produced and packaged into specialized lysosome-related organelles called melanosomes134. The protein produced by GPR143 gene is thought to regulate the segregation of melanosomal and lysosomal development pathway from their common precursor24. Tyrosinase and the other essential enzymes for melanogenesis are produced in rough endoplasmic reticulum and are transferred to early stage form of melanosomes to facilitate their maturation with increased melanin deposition. Once these organelles are filled with melanin, melanogenesis is halted by GPR143 signaling,175 and melanosomes are transported from melanocyte to its neighboring keratinocytes. In the skin of a Caucasians, each melanosome is incorporated into multiple small membrane-bound clusters and eventually degrade, whereas melanosome in individuals with darker skin remains as a single large organelle inside the keratinocyte45,116,163.
The biosynthesis pathway of melanin in melanosome starts with the hydroxylation of tyrosine to dihydroxyphenylalanine (DOPA) by tyrosinase. DOPA is then converted into DOPAquinone, which is also catalyzed by tyrosinase. From then on, the pathway splits depending on the subtype of melanin produced. For synthesis of eumelanin, DOPAquinone is spontaneously oxidated to become DOPAchrome, which is then either converted to 5,6- dihydroxycarboxylic acid (5,6-DHCA) by DOPAchrome tautaomerase (tyrosinase-related protein 2 or TYRP2) or spontaneously oxidated to produce 5,6-dihydroxyindole (5,6-DHI) to produce the final end product, eumelanin. On the other hand, pheomelanin is produced from DOPAquinone with the presence of cysteine or glutathione (Figure 1).
As outlined above, tyrosinase is a crucial rate-limiting enzyme involved in catalyzing multiple steps of melanogenesis. The phenotypical hypopigmentation seen in albinism is due to reduced tyrosinase activity43. Tyrosinase is a transmembrane monophenol monooxygenase. Synthesis of tyrosinase begins in the endoplasmic reticulum and is further modified in the Golgi apparatus. Mature tyrosinase is then transported to melanosomes where it catalyzes melanogenesis. Copper is a cofactor for tyrosinase, which ensures the enzyme is not active before reaching the melanosome. Several subtypes of OCA possess genetic mutations that lead to the retention of tyrosinase in the endoplasmic reticulum or disrupted delivery to the melanosome32,167.
III. Genetic Subtypes of Albinism
A. Oculocutaneous Albinism Type 1
OCA1 is an autosomal recessive disorder caused by mutation in TYR129. TYR is located on chromosome 11q14.3, spans 5 exons, and codes for the enzyme tyrosinase that contains 529 amino acids. Over 100 mutations have been reported at this locus. The severity of phenotypes vary depending on the level of impairment on tyrosinase activity155. In OCA1A misfolding of protein coded by mutant gene causes tyrosinase retention in endoplasmic reticulum and complete absence of tyrosinase activity, resulting in a profound lack of pigmentation in affected individuals12,34,165. OCA1B is caused by certain missense or hypomorphic mutations in TYR111. People affected by OCA1B may be indistinguishable from those with OCA1A at birth, but pheomelanin accumulates with increased age as there is some residual tyrosinase activity100. OCA1 Minimal Pigment (OCA1MP) has decreased tyrosinase activity allowing some pigmentation that increases with age and contrasts with OCA1B as it has life-long negative DOPA staining of hair bulbs84.
B. Oculocutaneous Albinism Type 2
OCA2 is caused by mutations in the pink-eyed dilution gene, OCA2 gene (also known as the P gene), that has 23 coding exons and 1 non-coding exon spanning 345kb at 15q11.2-q1298. OCA2 codes for a melanosomal membranous protein that regulates trafficking of tyrosinase and tyrosinase related protein-1 and thus affects melanin production164. In normal individuals, non-pathological polymorphisms of OCA2 have been shown to determine skin and iris color100. Defect in OCA2 has been shown to cause tyrosinase to accumulate in the endoplasmic reticulum or Golgi apparatus and is eventually secreted from the cell, rather than reaching melanosomes107,166. Phenotypically, OCA2 is milder than OCA1, but the spectrum of pigmentation is broad, ranging from almost no cutaneous pigmentation to virtually normal
128. Visual dysfunction is also less severe compared to OCA156. OCA2 is the prevalent subtype in Africa105,139. As the loci of OCA2 is close to the genes responsible for Angelman and Prader-Willi syndrome on chromosome 15, 1% of patients with these syndromes show hypopigmentation97.
C. Oculocutaneous Albinism Type 3
OCA3 results from autosomal recessive mutations at the gene locus that encodes the protein tyrosinase related protein-1 (TYRP1)17,108. The TYRP1 gene has 8 exons and spans 15-18kb on chromosome 9p2329. TYRP1 catalyzes eumelanin formation165, contributes to tyrosinase stabilization and melanosome structure77,109, and plays a role in determining melanocyte proliferation and apoptosis76. OCA3 was only reported in African blacks, but more recently has been described in other populations177. Phenotypically OCA3 are categorized into brown or rufous albinism. Patients with brown albinism have light brown hair and skin, and blue- green to brown irides, whereas those with rufous type present with red-bronze skin, ginger hair, and blue-brown irides108.
D. Oculocutaneous Albinism Type 4
Autosomal recessive mutations at the SLC45A2 is responsible for OCA4121. SLC45A2 has 7 exons and spans 40kb on chromosome 5p13.3. This gene encodes the membrane-associated transporter protein reported to facilitate tyrosinase transport and melanosome function14.
OCA4 was initially reported in a Turkish patient and has since been identified as the most common subtype in Japan71,121.
E. Oculocutaneous Albinism Type 5
OCA5 was first reported in a consanguineous Pakistani family. The gene responsible is yet to be identified, but has been mapped to chromosome 4q2481.
F. Oculocutaneous Albinism Type 6
Wei and coworkers first identified mutation in SLC24A5 gene on chromosome 15q21.1 in a Chinese patient with the clinical phenotype of non-syndromic OCA, and the condition was termed OCA6169. SLC24A5 encodes the transporter protein NCKX5 shown to affect cholesterol levels in melanocytes and in turn regulate tyrosinase levels61.
G. Oculocutaneous Albinism Type 7
OCA7 was first reported by Grønskov and coworkers in a consanguineous family from the Faroe Islands of Denmark55. The patients affected had a nonsense mutation in the LRMDA gene located on chromosome 10q22.2-q22.3 and facilitates melanocyte differentiation55.
H. Ocular Albinism Type 1
The X-linked recessive Nettleship-Falls ocular albinism (OA1) is the result of mutation in GPR143 gene on chromosome Xp22.3-22.210 with an estimated prevalence of 1 in 50,000127. GPR143 codes for G-protein coupled receptor (GPCR), a protein that controls the transport of melanosome in cells. Number and size of melanosomes were reported to be affected in patients with OA1100. Clinically, patients with OA1 have severely impaired vision, iris transillumination, hypopigmented skin macules, and the histological feature of macromelanosomes on biopsy of these skin segments147. As an X-linked recessive disorder, only males exhibit full phenotypes; however, because of lyonization of one X chromosome, carrier females could also show signs such as mud-splattered fundi and hyperpigmentation of peripheral retina28.
IV. Clinical Assessment of Albinism
Ophthalmic manifestation of albinism includes non-progressive reduction of VA, nystagmus, strabismus, abnormal decussation of retinal ganglion cell axons at the optic chiasm (Figure
2b), photophobia and iris translucency (Figure 2c), foveal hypoplasia, fundus hypopigmentation (Figure 2d), and abnormal head posture (AHP)56,110,128. Assessment on skin hypopigmentation and systemic review on bleeding susceptibility, history of recurrent infections, breathing difficulties, and colitis help to exclude syndromic form of albinism.
Owing to the heterogeneity of symptoms and signs and possible clinical sequelae, a multi- disciplinary approach involving a low vision specialist and dermatologist is important in optimizing refractive potential and improving quality of life for patients with albinism. For syndromic forms of albinism, a wider team should be involved that includes a general physician and/or a pulmonologist.
A. Refraction
Albinism is frequently associated with refractive error, with hypermetropia generally being rmore common than myopia174. Astigmatism is also regularly identified in albinism, predominantly with-the-rule astigmatism170. Schweigert and coworkers found that mean astigmatism significantly changes between birth and 10 years of age in albinism148. Thus highlighting the importance for children with albinism to have frequent cycloplegic refractions, particularly during the first decade of life to ensure prompt correction of refractive error.
B. Assessment of Nystagmus
Careful clinical assessment of nystagmus includes noting the axis of oscillation at the nine cardinal points of gaze direction, conjugacy, frequency, and amplitude125. Foveation period is the segment of slow phase of the nystagmus waveform when the eyes remain fixated with little or no movement, and the patient’s VA is better30,39. Modern video-based eye movement recordings (EMR) provide a non-invasive modality to analyze the details of nystagmus waveform even when the oscillation is not visible to the naked eye, and eye tracking data can be helpful for surgical planning31. The nystagmus in albinism is conjugate and horizontal with an accelerating slow phase. The presence of other waveforms on EMR would suggest other etiologies89. Higher proportions of jerk waveforms and reduced frequency have also been reported in albinism-associated nystagmus compared to FRMD7-associated infantile nystagmus89.
Null-zone is the field of gaze in which ocular instability is minimal, and vision is at its best. If the null-zone is not in primary position, as a compensatory mechanism, patients often
adopt an AHP in an attempt to place the eyes in the null zone2. AHP can also arise when patients struggle to view through refractive correction through the correct visual axis. AHP and involuntary head shaking can be noted while observing the child at play, while the magnitude of AHP, effect of near/distance fixation, and with/without refractive corrections on head positions can then be further assessed135. A number of devices that aim to objectively measure AHP have been developed, including torticollometer166, Harms’ wall62, and orthopedic goniometer117. Currently there is no standardized measurement125.
C. Orthoptic Assessment
Orthoptic examination in children with nystagmus associated with albinism is essential, as they have a higher risk of developing strabismus in comparison to those with idiopathic nystagmus23,89 On average, half of all patients with albinism have strabismus, but the prevalence is almost 100% in OCA1 patients64. Cover test should be performed with/without refractive correction and AHP at near or distance fixation, followed by alternating prism cover test for measurement of deviation. Ductions and versions in nine cardinal position of gaze, along with convergence with refractive correction and AHP, should be tested while noting any change in nystagmus125. Concomitant eso- or exotropia are the most common forms of ocular misalignment in albinism, though other motor components of esotropia such as alphabet patterns have also been reported64.
D. Visual Evoked Potentials
Visual evoked potentials (VEPs) are able to detect misrouting of visual pathway and can serve to confirm suspicion of albinism if clinical signs are unclear20,114. In albinism, there is an abnormally high number of ganglion cell axons from the temporal hemiretina decussating at the optic chiasm along with the normal crossing from the nasal hemiretina, resulting in an overall increase of retinal fibers from one eye projecting toward the contralateral visual pathway22. Recording of monocular VEPs from both eyes are compared, and a characteristic “crossed asymmetry” can be observed42,85. Multichannel pattern-reversal VEP is the recommended method of recording for chiasmal misrouting (Figure 2b) according to the International Society for Clinical Electrophysiology of Vision standards126. A summary of the
investigations, critical signs and differential diagnoses for each of them are shown in Figure 3.
E. Optical Coherence Tomography
Optical coherence tomography (OCT) is the investigation of choice for assessing the retinal abnormalities present in patients with albinism as it is quick and non-invasive. Foveal hypoplasia has long been considered a universal abnormality associated with all subtypes of albinism112. Degrees of hypoplasia can be graded using a standardized system described by Thomas and coworkers161 (Figure 4) that describes the degree of arrested retinal development and thus provides an indication of visual prognosis. This grading system has been recently validated in preverbal children with nystagmus and is able to predict future vision144. Sheth and coworkers have also demonstrated that iris OCT has potential to be a diagnostic tool as the posterior epithelial layer thickness of iris is abnormal in albinism151.
F. Genetic Testing
Diagnosing and differentiating subtypes of albinism based on clinical presentation alone is challenging as there are considerable overlapping features, e.g. OCA1B is clinically similar to OCA2. Thus genetic testing is helpful for confirming clinical suspicion, especially in children with poor cooperation where other clinical diagnostic modalities are difficult to perform162. For genetically diverse disorder like albinism, performing Next-Generation Sequencing (NGS) is more cost-effective than traditional Sanger sequencing and has emerged as the frontline genetic diagnostic tool130,162 (figure 5). Furthermore, the genetic information on causative pathological variants is vital for carrier testing of the family member, prenatal/preimplantation diagnosis, and genetic counseling162. Lasseaux and coworkers report that in 12% of patients with a clinical diagnosis of albinism only one heterozygous mutation was identified, while in 16% no mutations in known albinism genes are identified91. The could be due to the significant phenotypic overlap with other disorders87,162, deep intronic variants missed by next generation sequencing,58,162 and additional genes associated with albinism that are yet to be identified.
V. Treatment Options for the Clinical Problems Arising from Albinism
A. Strategies on Optimizing Visual Acuities
Low vision aids may be useful in some cases of albinism, typically issued following full refractive correction. Magnification apparatuses such as telescopes and near magnifiers may be employed in cases of significantly reduced VA. Omar and coworkers described an individual with albinism who benefitted from a bi-level telemicroscopic apparatus that improved distance VA from 6/48 for both eyes to 6/9 for both eyes131. This demonstrates that
low vision aids may be considered a therapeutic tool in cases of albinism where VA remains poor following refractive correction
Anisometropic and ametropic amblyopia may develop in albinism156. This reinforces the importance of prompt correction of refractive error in order to reduce the potential for amblyopia. If amblyopia is present following a refractive adaptation period of 16-18 weeks, occlusion therapy should commence156. In some cases of albinism, manifest latent nystagmus (MLN) may also occur1,44. In the presence of MLN, atropine, which allows light stimulation, may be the preferred type of occlusion.48,89.
B. Management of Nystagmus and its Sequelae
VA of patients with albinism can be improved by treatments that aim to reduce the intensity of the nystagmus, lengthen the foveation periods in the null zone, or correct AHP by moving the null zone into primary position. In 1960, a four-muscle large recession procedure involving recessing the horizontal recti to the equator of the globe was described and showed benefit in improving visual function in patients with nystagmus13. Helveston and coworkers first reported a case series of 10 patients with congenital nystagmus (2 had OCA) receiving four-muscle large recession (11-13mm)63. In this cohort, 7 patients had on average a 1-line (Snellen) improvement in VA. On comparison of pre- and post-op video recording, 80% of the patients had reduced intensity of nystagmus.
Degrees of deviation of head posture in 3 out of the 5 patients with pre-operative AHP improved by 10 ° to 25° post-operatively63. In a series published by Davis and coworkers, 12 patients with albinism-associated nystagmus underwent large retro-equatorial four-muscle recession, and 83% of the patients had 1 line (Snellen) improvement in VA, while 58% had 2 lines of improvement37. Atilla and coworkers found improvement of VA by average of 1 line in 3 out 5 patients with OA-associated nystagmus and reduced nystagmus intensity in all 5 after four-muscle large recession (7-10mm)7.
AHP can have a significant impact on quality of life, causing neck problems, headache and cosmetic issues136. If the AHP is preventing children with low VA to look through their glasses, they are at risk of developing amblyopia. In 1953, Kestenbaum and Anderson independently proposed surgical procedures that aim to shift the null-zone to primary position, thereby alleviating AHP4,82. The procedure described by Kestenbaum involved
paired recessions and resection of all four horizontal rectus muscles82. Its modified version by Parks is the most commonly performed surgery for AHP137; however, the reported long-term outcome of this procedure was variable as some patients redeveloped AHP. Subsequently, Parks approach was augmented by various authors, though there were still high rates of recurrence, under-correction, and risk of developing secondary ocular misalignment reported26,79,95,117,120,149. In Anderson’s case series, 4 patients with congenital nystagmus underwent recession of the yoke rectus muscles that move the eyes in the direction of the tonically deviated gaze and achieved reduced nystagmus and AHP post-operatively4. The efficacy of the Anderson procedure was later confirmed by various authors, though over- correction and limitation of ductions developed following large recessions5,16,59. In a series of 27 patients (9 with OCA), Yahalom and coworkers reported decrease in angle of AHP by an average of 7.2° following surgery, with complete resolution in 14 patients173. The Anderson- Kestenbaum procedure is the standard surgical approach for AHP.
Another procedure, the four-muscles tenotomy, involves detaching and reattaching the horizontal rectus at the same insertion site without recession or resection40. The theory is that the removal of tendon organs responsible for proprioception would improve nystagmus. In a prospective series reported by Hertle and coworkers, 15 patients with albinism had extraocular muscle surgeries with variable degrees of resections/recessions or tenotomy, and 93% of the cohort had demonstrated 0.1 LogMar of improvement in VA. After surgery, head posture was improved in the 9 patients with pre-operative AHP, and the null zone was also significantly broadened65. Hertle and coworkers later reported another series of 75 patients with congenital nystagmus (15 had albinism) undergoing resections/recessions surgery or tenotomy66. After operations, this cohort had in average 0.2 LogMar of improvement in VA and 16.1° of increase in null zone width. Contrary to the aforementioned evidence on benefits of extraocular surgeries, Villegas and coworkers showed that correction of strabismus by resections and recessions had provided no significant changes for VA nor nystagmus in a cohort of 13 albinism patients (8 had OCA, 5 had HPS)167.
Some patients with albinism-associated nystagmus present with a predominantly vertical AHP in addition to a horizontal component. In a prospective series reported by Hertle and coworkers, 24 patients (13 had albinism) with predominantly vertical AHP underwent vertical extraocular muscles surgeries in addition to horizontal muscles recession/resection.The 13 patients with a chin-down posture had a bilateral superior rectus
recession and inferior oblique myectomy, while the 11 patients with a chin-up posture had bilateral superior oblique tenectomy and inferior rectus recession67. At 6-month post-surgery, the cohort’s vertical component, as well as the horizontal component, of head posture improved, but did not resolve completely. VA also improved by 0.2 LogMar on average67.
More recently, in a series of 7 patients with congenital nystagmus (4 had OCA) who underwent vertical extraocular muscle surgery to correct vertical AHP, Kumar and Lambert demonstrated that all but one patients achieved improvement or even complete resolution of AHP postoperatively, which persisted for a median 8 years follow up90.
Pharmacological strategies has also been used in the treatment of congenital nystagmus. In a double-masked RCT, McLean and coworkers compared the impact of gabapentin or memantine on visual function in 16 patients with congenital nystagmus. In the gabapentin group 6 had albinism; in the memantine group 7 had albinism) to 15 patients in the placebo group (6 had albinism)113. Although VA improved significantly in patients with idiopathic congenital nystagmus, the change in those with a secondary cause, i.e. albinism, was not statistically significant113; however, nystagmus intensity and foveation were improved on eye movement recordings after medication in all subjects113. More recently, in a series of 18 patients with congenital nystagmus (5 had albinism), Aygit and coworkers demonstrated the potential benefit of topical carbonic anhydrase inhibitors. Nystagmus decreased in 5 patients, AHP was reduced in 4 patients, and VA improved in 9 patients8; however, the observed improvement in VA was not statistically significant.
One limitation of correcting refractive error with glasses in people with albinism is the presence of nystagmus impeding on the ability to view through the correct visual axis. The introduction of contact lenses (CLS) to correct refractive error may benefit individuals with nystagmus by increasing the proportion of time looking through the correct visual axis38. CLs may dampen congenital nystagmus in some patients attributed to additional vergence and accommodative effort exerted with CL wear15,54; however, the relative benefits of soft CL or rigid gas-permeable CLs in comparison to spectacles remains debatable. Biousse and coworkers investigated the therapeutic effect of soft CLs on 4 individuals with congenital nystagmus, 2 of whom were affected with albinism15. All 4 individuals demonstrated a slight improvement in VA and contrast sensitivity; however, a dampening effect on the nystagmus was not observed. All individuals did, however, comment on an overall improvement in quality of life and a perceived improved visual function with CL wearing in comparison to
spectacle wear15. A randomized-controlled trial of 24 patients with infantile nystagmus (12 idiopathic, 12 albinism) demonstrated soft CL leading to a statistically significant deterioration in visual function in comparison to rigid gas-permeable lens and spectacles74. There were no statistically significant differences in nystagmus characteristic detected between soft or rigid CL and spectacles.
C. Reducing Glare
The lack of intact iris pigment epithelium in patients with albinism cause them to suffer from disabling glare, which also results in impaired VA56. Surgical implants have been developed to reduce photophobia. Wong and coworkers reported that black-diaphragm IOL implantation during cataract surgery was capable of reducing subjective glare and photophobia in a retrospective series of five patients (1 had OCA) with iris deficiency172; however, postoperative complications including choroidal detachment and glaucoma were reported in 2 patients. Moreover, black-diaphragm IOL is known to be difficult to manipulate because of its rigidity and brittleness6,140.
An alternative to a single-piece black-diaphragm IOL is a prosthetic iris implant without a central lens. Implantation of 2 multiple-fin black rings (Morcher Aniridia Implants) in the capsular bag reduced light entering the posterior segment and therefore glare25. The iris implant allows insertion via small incision and, as it is placed endocapsularly, risks of inflammation and glaucoma are smaller; however, this iris implant is susceptible to fracture because it is constructed with brittle material. In a series of 13 eyes of 8 patients with albinism receiving either the multiple-fin black rings implant or the single-piece color- diaphragm IOL device, 8 eyes showed improvement in VA, and glare was reduced subjectively in 6 patients80.
The various designs of modified contact lenses (CL) have been employed as a non-surgical intervention for reducing glare in albinism. As early as 1959, the first opaque corneal contact lenses with a layer of painted iris containing a clear refractive zone was described52. Later, Espy reported a scleral CL with painted iris for patients with OA46. More recent developments have investigated the use of tinted soft CL to imitate artificial iris. Saeed and coworkers noted that VA and nystagmus intensity were significantly improved with tinted CL wear and that these improvements increased or were maintained following 6 months of continued use and observation145. Omar and coworkers found that a prosthetic CL (Flexcon)
with 3.5 mm clear refractive zone in the central pupil surrounded by 12 mm of tinted iris area reduced glare subjectively in a 21-year-old patient with albinism131.
D. Novel Therapies that Directly Address the Molecular Errors of Albinism
Previous researches have established that, the failures of melanin biosynthesis and alterations in pigmentary pathway in the RPE are linked to the abnormal development of the neural retina in albinism33,51. L-DOPA is a vital amino acid generated by TYR during melanin biosynthesis and the lack of which is suggested to be the key to the retinal pathology seen in albinism92. OA1 has been shown to be selectively activated by L-DOPA, and OA1 activity stimulates pigment epithelium-derived factor (PEDF) secretion by RPE, a molecule that supports retinal development73,103. This evidence led to the hypothesis that L-DOPA generated by TYR in melanin biosynthesis pathway regulates normal retinal development via OA1 signalling, and provision of exogenous L-DOPA is a potential pharmacological intervention to enhance retinal neural development for patients with OCA (but not OA).
Summers and coworkers examined if oral levodopa with carbidopa would improve VA in patients with OCA in a double-masked RCT157. In this trial, 45 patients (mean age 14.5 years, range: 3.5 to 57.8 years) with OCA (12 had OCA1A, 18 had OCA1B, 14 had OCA2, 1 had HPS) were randomly assigned to receive levodopa 0.76 mg/kg with 25% carbidopa, levodopa
0.51 mg/ kg with 25% carbidopa, or placebo. After 20 weeks of follow-up, although no serious adverse event was reported, neither dose regimens significantly improved VA in these patients compared to placebo157. While the development of the decussation of retinal ganglion cell axons at the optic chiasm are determined prenatally, foveal maturation continues postnatally. This residual plasticity of the retina thus offers a potential therapeutic window93. Lee and coworkers argued that L-DOPA supplementation within a postnatal
therapeutic window potentially could rescue the developing retina in children with albinism94. In a murine model of OCA1, they demonstrated that L-DOPA treatment at birth or 15 days of age can rescue retinal morphology based on OCT measurements and retinal function evident by electroretinogram (ERG).
As retinal development relies on normal pigmentary pathways of the RPEs, it is postulated that increasing pigmentation in patients with OCA may aid maturation of the retina, alongside with reducing glare and photophobia, thereby improving visual function132. Animal studies have suggested increasing level of tyrosine helps to stabilize TYR and increase pigmentation of the subjects143. Nitisinone is an FDA-approved drug for the treatment of
hereditary tyrosinemia type-1, a rare inborn error of tyrosine catabolism35. Due to deficiency of fumarylacetoacetase, the enzyme involved in the last step of tyrosine degradation pathway, toxic intermediate metabolites such as maleylacetoacetate, fumary- lacetoacetate, and succinylacetone accumulate. Nitisinone inhibits tyrosine degradation by competitively binding to 4-hydroxyphenylpyruvate dioxygenase, an enzyme upstream of fumarylacetoacetase in the tyrosine catabolic pathway, thereby reducing the level of toxic metabolites35. As nitisinone treatment blocks the breakdown of tyrosine, plasma level of tyrosine is also elevated. Onojafe and coworkers first proposed nitisinone’s property of increasing tyrosine level could be exploited to augment pigmentation in albinism; based on transgenic murine models of OCA1B, a 1-month course of nitisinone dose of 4mg/kg given every other day orally was able to elevate tyrosine levels and increase pigmentation in areas of new hair growth132; however, a later study revealed that nitisinone was not able to demonstrate the same favorable effect on fur or eye pigmentations, nor increase melanin production in murine models of OCA3133. More recently, the same research group reported a human trial of nitisinone3. In this pilot study, 5 adult patients with OCA1B were treated with 2mg a day of oral nitisinone for 1 year. Skin and hair reflectometry revealed significant increase in pigmentation on the inner bicep and hair respectively after the treatment; compared to baseline. Overall the improvement in VA was statistically, but not clinically, significant. No adverse drug reaction occurred; however, no significant change in iris or fundus pigmentation was observed, likely because the ocular structures of adults are largely mature3.
E. Emerging Gene-based Applications for Albinism
Gene therapy has demonstrated clinical success in treating inherited retinal diseases27. Adeno-associated virus (AAV) is a small single-stranded DNA virus of the parvoviridae family, and AAV-based vectors are able to transfect retina efficiently in animal models and
human without apparent toxicity70. The application of AAV-based gene therapy for OA1 was first reported by Surace and coworkers.158 OA1 gene encapsulated by AAV-vectors were delivered subretinally via a transscleral approach to the adult Oa1-/-mice (OA1 murine models)158. After 4 weeks, ERG demonstrated higher, though not statistically significant, b- wave amplitude under photopic conditions and significantly higher a- and b-wave amplitudes under scotopic conditions in treated mice. Moreover, melanosome density in the RPE of treated mice was higher than controls158. These findings suggest OA1 gene via AAV-vectors can partially rescue of electrophysiological abnormalities and modify RPE structure, even in
adult subjects. Subretinal injection of AAV-vector harboring human TYR gene was an effective genetic modulation for OCA1 in a murine model49. Pigmentation was evident in the retina of treated subjects with a significant increase in melanosome density in the RPE. The ERG of treated retina also suggested restoration of retinal functions. These data demonstrate the potential benefit of AAV-based gene intervention for albinism in animal models.
The bacterial clustered regularly interspaced short palindromic repeats and CRISPR- associated nuclease protein (CRISPR/Cas9) system is an efficient gene editing technology that has revolutionized molecular biology, offering simple ways for precise gene editing and multiplex gene editing75. With a CRISPR/Cas 9 system, a double-strand break can be created at a specific site of the targeted DNA sequence and the donor nucleotides with desired mutations can be incorporated at the target site by homology-directed repair176. Song and coworkers first demonstrated CRISPR-based genetic edition of TYR gene on animal level.
SsDNA with nucleotide C instead of A at position 1118 in codon 373 of TYR gene was microinjected into embryos of New Zealand white rabbits, which have inherent TYR mutation and albinism phenotypes154. The mutant offspring exhibited elevated melanin production in hair follicles and irises154. Future study investigating the clinical feasibility of utilizing CRISPR/Cas9 system for correcting the genetic error of albinism is required. Additionally, Fukai and coworers have suggested that the aminoglycoside-induced translational read- through effect in suppressing nonsense mutation can be used therapeutically for intervening mutations commonly found in albinismA; however, no in vivo study has been published to date.
F. Skin Protection
Ultraviolet radiation (UVR) on skin produces DNA damage, gene mutations, immunosuppression, oxidative stress and inflammation- all of which contribute to the pathogenesis of skin cancer21,119. Epidemiological studies show strong inverse correlation between the skin pigmentation and the incidence of sun-induced skin cancers60. The low incidence of skin malignancies in darker skinned groups is due to the photoprotective properties of epidermal melanin, which is believed to provide an inherent sun protection factor (SPF) of 1.5-2 and for heavily pigmented individuals, as high as 1321,53,83.
The production of the photoprotective melanin, eumelanin, is minimal in OCA150. Sequelae of skin cancer is the main cause of early death in patients with albinism36. There is a strong
association of cutaneous carcinomas with OCA1 and OCA2123. Squamous cell carcinoma (SCC) is the most common skin cancer among OCA patients104 and most commonly affects the sun-exposed head and neck. Patients with albinism in sub-Saharan Africa are 1000-fold more likely to develop SCC compared to the general population106 and by the third decade of their life, many will have developed potentially fatal SCCs99. SCCs in albinism tend to run a more aggressive course with a higher recurrence rate after treatment than they do in normally pigmented persons99. Evidently, people with albinism are highly vulnerable to the harmful effects of UVR, and it is crucial to educate them about the importance of skin protection through sun avoidance, barrier protection, and sunscreen use.
Avoiding sun exposure helps minimize UVR-induced damage68. The strongest radiation reaches the earth in the summer month, between 10am to 5pm , which is when the UVR falls perpendicularly152. Hence, morning and evenings are the best time to arrange outdoor activities to minimize UV exposure. Numerous national weather forecasting services provides daily UV index forecast in the scale of 1 (low) to 10/11 (high/extreme). This is a useful tool that helps people to take necessary precautions to reduce the negative impact of UVR on skin50. For every 300m above sea level UVR intensity increases by 4%. Snow reflects 90% of UVR whereas sand reflects 15-30%152. Water also strongly reflects UV rays and could cause photodamage to less exposed areas such as underneath the chin or nostrils.
Moreover, correct choice of clothing can provide good protection against UVA and UVB. Synthetic materials should be chosen over natural fibers as they block UVR more effectively152. There are also new fabrics available that are specifically designed to offer high sun protection against both UVA and UVB124. Wide-brimmed hats and sunglasses are also recommended to protect the facial skin9,50,88,115.
Sunscreens with at least a SPF of 30 that protects against both UVA and UVB are generally recommended for people with albinism47; however, the use of sunscreen should correlate with skin pigmentation and the ability to tan. For instance, for individuals with OCA1A with complete devoid of melanin, sunscreens with a high SPF value of 45-50+ are recommended123. Sunscreen should be applied 20 minutes before sun exposure, and the recommended sunscreen application thickness to achieve the labeled SPF is 2mg/cm2. Yet studies reveal that, in real practice, people apply only 20-50% of the thickness required, and
thus frequent reapplication within one hour is recommended to obtain a thicker sunscreen layers to achieve increased skin protection138.
Finally, early pediatric dermatology consultation and parental education on skin protection and cancer prevention are warranted, with an important long-term goal of improving the outcome in children with albinisms102. Annual to biennial total body skin examination is likewise recommended to screen for evidence of sun-related skin damage and pre-cancerous or cancerous lesions, especially in areas of high intensity or prolonged sunlight exposure11,41,101,102,159. Dermatologists should have a low threshold of suspecting cancer in this vulnerable population as early detection and treatment of skin cancers will reduce morbidity and mortality.
VI. Conclusion
Treatment for albinism has previously focused on managing the associated clinical features and possible clinical sequelae. This includes improving nystagmus using both surgical and pharmacological treatments, optimizing vision using appropriate refractive correction, strabismus and anomalous head posture surgery, skin protection and treatment modalities to reduce glare. Pre-clinical models and early treatment trials have shown promise at targeting biochemical pathways for both retinal development and improving melanin biosynthesis.
Thus, these emerging therapies have the potential to have translational benefit for patients with albinism.
VIII. Method of Literature Search
All studies included in this review were collated through online databases PubMed and Scopus using the search terms “albinism”, “treatment”, “surgery”, “gene therapy”, “refraction”, “vision aid”. Promising studies listed in selected articles were also reviewed for potential inclusion. Inclusion criteria includes availability in English full text, relevancy to albinism, quality of the data and if the studies have been cited by other publications.
Disclosure
‘Conflicts of interest: none’.
Figure 1. Schematic pathway of melanin biosynthesis in melanosome. Initial steps of melanin synthesis are catalyzed by tyrosinase to produce DOPAquinone. Further enzymatic actions lead to production of two types of melanin. DOPAchrome tautaomerase (TYRP2) promotes synthesis of eumelanin, whereas action of glutathione and cysteine supports pheomelanin synthesis. DOPA= dihydroxyphenylalanine; 5,6-DHCA=5,6- dihydroxycarboxylic acid; 5,6-DHI=5,6-dihydroxyindole.
Figure 2: 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). Thus, a subtracted waveform (1–5 and 2–4) would show no significant polarity differences as seen in the idiopathic infantile nystagmus (IIN) patient or a healthy volunteer (a). However, in a patient with chiasmal misrouting as seen in albinism asymmetric responses are seen (blue arrow) (b). Different degrees of iris transillumination defects seen with albinism (c). Pale fundus associated with albinism (d). (Reproduced 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. Eur J Hum Genet.
2017;25(6):725-734. doi:10.1038/ejhg.2017.44.)
Figure 3: The outline of investigations in a patient suspected with albinism are shown. The characteristic sign that should be elicited with each investigative modality and differential diagnoses are shown. FHONDA = foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis; ONH = optic nerve hypoplasia; IIN = idiopathic infantile nystagmus; OCA= oculocutaneous albinism; OA = ocular albinism; EMR = eye movement recordings.
Figure 4: Foveal hypoplasia grading scheme using optical coherence tomography (OCT).
Top panel shows features of foveal specialization seen on OCT. Grades 1 – 4 are seen in
typical foveal hypoplasia where different degrees of foveal specialization are seen. Grade 4 foveal hypoplasia has no evidence of specialization and resembles peripheral retina. Grade 3 foveal hypoplasia has only outer nuclear layer (ONL) widening. Grade 2 foveal hypoplasia has outer segment (OS) lengthening in addition to ONL widening. Grade 1b foveal hypoplasia has a very shallow pit (or indent) in addition to specialization features seen in grade 2. Grade 1a foveal hypoplasia has a near normal foveal pit (however with the presence of inner retinal layers posterior to the foveola) and all other features of specialization seen in grade 2. Atypical foveal hypoplasia is characterized by disruption of the inner segment ellipsoid (ISe) and a shallow foveal pit. 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. (Adapted and reproduced 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.)
Figure 5: Diagnostic workflow for patients with nystagmus. Using next generation sequencing using a targeted panel as a frontline diagnostic tool has the potential to obviate the need for other investigations. Traditionally, patients would undergo several different investigations prior to being able to identify the underlying etiology. The order of performing investigations vary between centers, depends on the clinical context, patient cooperation and availability. Some of the limitations associated with each investigative modality is shown in the box. Not all patients would undergo MRI scans; however, it is one of the investigations of choice for specific forms of nystagmus (for eg, vertical nystagmus) or the presence of additional neurological features such as ataxia were noted. The recently proposed pathway using NGS would help establish a genetic diagnosis and thus guide further investigations and targeted treatment. (Reproduced 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. Eur J Hum Genet. 2017;25(6):725-734. doi:10.1038/ejhg.2017.44.)
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