Variants and Management of Albinism.pptx

Albinism

1. Albinism Dr. Fashola M.B.

2. Outline Introduction Epidemiology Etiology Genetic classification Features Associations Management Conclusion References

3. Introduction Albinism is a group of inherited disorders in which there’s little to no production of melanin. Essentially clinical diagnosis, presenting as pigmentation abnormality in the skin, hair, and/or eyes. It can result in significant vision abnormalities and also predisposes to sunburn and skin cancers. The degree of presentation depends on the genetic type of albinism, of which there are two main types, Oculocutaneous albinism and Ocular albinism.

4. Epidemiology Worldwide: Prevalence of 1 in 5,000 to 1 in 40,000. 1 in 37,000 in America, higher in African-American communities. 1 in 18,000 in China. In Africa, rates are generally higher, at 1 in 4000–5000 and about 1 in 1000 in some communities. Prevalence can change over time, in various geographical regions of the same country, according to prevailing cultural norms.

5. Epidemiology Clinico-epidemiologic features of oculocutaneous albinism in north-eastern Cairo – Egypt. Genetics Clinic, Paediatric Hospital, Ain Shams University, Cairo, Egypt. 1 per 5843 patients attending the Paediatric hospital over a period of 43years had OCA. Consanguinity was reported among parents of 66.37% of patients & positive family history was reported in 46.01% of patients. Complete OCA was detected in 48.59% of patients, partial albinism in 41.59% of patients and syndromic albinism was detected in 7.96%

6. Epidemiology The Demographic, Geographic and Socioeconomic Survey of Persons with Albinism in Nigeria, 2018 – The Albino Foundation. This baseline survey was conducted simultaneously in 6 states (Lagos, Kogi, Enugu, Cross River, Kano & Adamawa) and Abuja. People with albinism aged 18-56+ years, total of 1,893 respondents. Females (55%) > Males (45%). The most predominant health condition is poor vision (31-54%); others skin related problems like freckles (20%).

7. Epidemiology In a population-based survey in Enugu state, between August, 2011 and January, 2012. The participants were enrolled at the Eye Clinics of the UNTH and Enugu State University of Science and Technology Teaching Hospital. N = 153; (males:70) were aged 23.5 + 10.4 SD years (range 6–60 years). Non-refractive disorders (nystagmus, foveal hypoplasia, hypopigmented fundi and prominent choroidal vessels) in 100.0 %; and strabismus in 16.3 %. Refractive errors comprised astigmatism in 73.2 % of eyes, myopia in 23.9 % and hypermetropia in 2.9 %. Spherical errors ranged from −14.00 DS to +8.00 DS while astigmatic errors ranged from −6.00 DC to +6 DC.

8. Aetiology Melanocytes are found in the skin, hair follicles, and pigmented tissues of the eye. Melanin is formed in the melanosome organelle of the melanocyte.

9. Aetiology The eye has 2 origins from which pigmented cells are normally derived: The neuroectoderm of the primitive forebrain is the origin of melanocytes in the retinal pigment epithelium, iris epithelium, and ciliary epithelium. The neural crest is the origin of melanocytes in the iris stroma, ciliary stroma, and choroid. The presence of melanin during ocular development is important. The fovea fails to develop properly if melanin is absent during development. Also, neural connections between the retina and the brain are altered if melanin in the retina is absent during development.

10. Aetiology Abnormal decussation at the optic chiasm.

11. Phenotypic Classification Tyrosinase negative (Severe) Albinism: Hair bulb incubation test negative for tyrosinase activity throughout life. Most severe visual symptoms, requiring low vision aids. Tyrosinase positive (Mild to moderate) Albinism: Hair bulb incubation test negative for tyrosinase activity at birth, becomes increasingly positive later in life. Less severe visual symptoms, visual acuity may be normal.

12. Genetic classification Oculocutaneous Albinism (OCA) Ocular Albinism (OA)

13. Genetic Classification OCA Subtypes Gene Position Affected Protein Mode of Inheritance OCA 1 OCA 1A (tyrosinase-negative OCA) OCA 1B (yellow-mutant) OCA 1TS (temperature-sensitive) OCA 1MP (minimal pigment) 11q14-21 Tyrosinase Autosomal Recessive OCA 2 (tyrosinase-positive OCA, brown OCA) 15q11-13 P protein Autosomal Recessive

14. Genetic Classification OCA Subtypes Gene Position Affected Protein Mode of Inheritance OCA 3 (red OCA) 9p23 Tyrosinase-related protein (TRP1) Autosomal Recessive OCA 4 5p13.3 Membrane associated transporter protein (MATP) = SLC45A2 Autosomal Recessive OCA 5 4q24 Unknown Autosomal Recessive OCA 6 15q21.1 SLC24A5 Autosomal Recessive

15. Genetic Classification OCA Subtypes Gene Position Affected Protein Mode of Inheritance OCA 7 10q22 C10orf11 Autosomal Recessive OA 1 (Nettleship-Falls type) X p22.3-22.2 GPR143 X-linked Recessive AROA Multiple gene loci Tyrosinase in some cases; P protein in some cases Autosomal Recessive OA 2 ( Forsius -Eriksson type) Xp21.3-p21.2 CACNA1F X-linked Recessive

16. Genetic Classification OCA1A: Tyrosinase negative. Absence of all pigmentation. Severe visual symptoms, V/A <6/60. Hair bulb stains DOPA negative throughout life. OCA1B (Yellow variant): Tyrosine positive, with decreased tyrosinase activity. Accumulates yellow pigment in eye, skin and eye over the years. OCA1TS (Temperature sensitive): Tyrosinase activity depending on skin temperature. May have normal vision.

17. Genetic Classification OCA 2: Tyrosinase positive Most common in Nigerians and Ghanians . Milder visual dysfunction. OCA 3: Tyrosinase positive Red/bronze skin Ginger (orange) hair Blue/brown iris

18. Genetic Classification Ocular Albinism (OA1) - Nettleship Falls : X-linked inheritance. 10% of all albinism; 1 in 50,000 – 1 in 150,000. Carrier females may show mild patchy features of albinism Hypopigmented macules on skin Decreased visual acuity Iris transillumination Mud-splattered fundus (scattered areas of depigmentation and granularity in mid-periphery) Male only affected.

19. Genetic Classification OA2 – Aland Island Eye disease Red-green colour defect Defective dark adaptation Female carriers have no characteristic eye defects. No demonstrable misrouting of fibre at the optic chiasma.

20. Features Skin & hair pigmentation anomalies. Iris pigmentation anomalies. Photophobia. Poor vision. Squint. Recurrent nose bleeds. Recurrent infections.

21. Features History of easy bruising or recurrent infections. Hearing difficulty in some forms of X-linked ocular albinism. Family history: positive for albinism and/or consanguinity.

22. Features Visual acuity: 6/12 to <6/60 Astigmatism Myopia Hypermetropia Amblyopia Ametropic Strabismic

23. Features Lid: Poliosis Actinic keratosis Squamous Cell Carcinoma Basal Cell Carcinoma

24. Features Strabismus. Exotropia Esotropia Heterochromia iridium.

25. Features Nystagmus (pendular) +/- head tilt.

26. Features Intraocular pressure: Association found with Axenfeld-Reigers anomaly. Megalocornea : In X-linked Ocular albinism.

27. Features Iris transillumination: speckled or diffuse.

28. Features Hypopigmented fundus. Visible choroidal vasculature. Foveal hypoplasia: absence of foveal pit. Decreased foveal cone density. Foveal avascular zone is absent, with vessels crossing the area 2disc diameters temporal to the optic disc margin.

29. Associations 1. Hermansky-Pudlak syndrome Autosomal recessive disorder Mutation in HPS1 gene on chromosome 10. Rare - 1:500,000 – 1:1,000,000 general population; 1:1800 in the Swiss or Puerto Ricans population. OCA, Platelet dysfunction (bleeding tendency), Interstitial lung disease, Granulomatous colitis.

30. Associations 2. Chediak -Higashi syndrome Autosomal recessive disorder. Mutation in lysosomal trafficking regulator in CHS1/LYST gene. Rare; <500 reported cases in literature. Infancy/Early childhood. OCA; Neutropenia with increased susceptibility to infections; Thrombocytopenia, peripheral neuropathy, seizures, gait disturbances.

31. Associations 3. Griscelli syndrome Autosomal recessive disorder. Mutation in MYO5A (type 1), RAB27A (type 2) & Mlph gene (type 3). Rare; Infancy/Early childhood. Silver hair, skin hypopigmentation, neurologic deficit, +/- immunologic deficit. Lack of azurophilic granules in neutrophils

32. Associations 4. Elejalde syndrome: Rare; reported only 10 times in literature. Infancy/Early childhood. Silvery hair, CNS dysfunction – hypotonia, hemi/quadriplegia, Seizure, Developmental delay. No immunologic disturbance.

33. Associations 5. Albinoidism Autosomal dominant mutation with incomplete penetrance Component of Prader-Willi syndrome. Reduction of melanocytes of neural crest origin (skin, hair, and iris stroma) and retention of normal retinal and iris pigment epithelia of neuroectodermal origin. There is no foveal hypoplasia, nystagmus, or photophobia, and visual function is normal. Pigmentation improves with time.

34. Associations 6. Waardenburg syndrome Autosomal dominant disorder Mutation in transcription factors PAX3 and MITF Piebald albinism, heterochromia irides, broad nasal root.

35. Investigations Full blood count with differentials. Blood film Bleeding time Skin histology: Macromelanosomes

36. Investigations Visual Evoked Potential : Measures the electrical signal generated at the visual cortex in response to visual stimulation. In albinism, non-symmetric pattern.

37. Investigations Macular Optical Coherence Tomography (OCT): uses low-coherence light to take cross-sectional images of the retina.

38. Investigations OCT Angiography: Absence of foveal avascular zone.

39. Management No Cure. Management is multidisciplinary and aimed at Improving vision. Limiting risk of skin cancer. Improving quality of life.

40. Management Genetic counselling: Family history is taken; The diagnosis, prognosis, and mode of inheritance is discussed; Recurrence risks are calculated; Reproductive options are given; Management of the medical and psychosocial aspects of the disorder are explained.

41. Management Lifestyle modification: Avoid exposure to sunlight. Use of sunshade and hats. Use of sunscreen. Correct refractive errors. Spectacles with tint and anti-reflex. Contact lens Laser corneal refractive surgery e.g. LASIK.

42. Management Low vision aids. Hand-held magnifiers Telescope Video magnifiers. Amblyopia treatment Correction of significant refractive error. Occlusion/Penalization therapy. Rehabilitation: School for the blind, vocational training.

43. Management Strabismus surgery. Recession Resection

44. Management Management of Nystagmus Non-Surgical Spectacles: Over-minus patient to stimulate accommodative convergence and therefore dampen nystagmus. Contact lens: better for high refractive errors. Surgical: To reduce the amplitude of the nystagmus by weakening the muscle fore of all 4 recti muscles. Kestenbaum surgery (Recession and resection of opposing recti) Anderson surgery (Recession of opposite recti)

45. Experimental treatment Nitisinone is an FDA-approved inhibitor of tyrosine degradation for hereditary tyrosinemia. Brooks and colleagues hypothesized that the relative deficiency of tyrosinase in OCA type 1 may be ameliorated by increasing the concentration of tyrosine with nitisinone and thus improving pigmentation with OCA 1. In mice studies, nitisinone indeed improved pigmentation in fur and irides, suggesting potential for benefit in humans affected by OCA 1.

46. Experimental treatment A group by Martinez-Garcia et al attempted to supplement L-DOPA , an intermediate metabolite of melanin synthesis pathway in mouse models. Various experiments suggested that L-DOPA supplementation may help overcome visual abnormalities associated with albinism. Phase 2 clinical trial is underway in the US to study the effects of L-Dopa supplementation in human subjects. A Japanese group suggested the use of aminoglycosides that can read through non-sense mutations for a potential treatment measure for common mutations found in albinism.

47. Conclusion Albinism is a genetically inherited condition, occurring in both genders, regardless of ethnicity, worldwide. Its visual effects can range from mild to potentially devastating. It is therefore essential that children with albinism are seen by an ophthalmologist early and regularly to allow proper optical correction of their errors and appropriate lifestyle modification.

48. References Mohamed, A. F., El-Sayed, N. S., & Seifeldin , N. S. (2010). Clinico -epidemiologic features of oculocutaneous albinism in northeast section of Cairo—Egypt . Egyptian Journal of Medical Human Genetics, 11 , 167–172. The Demographic, Geographic and Socioeconomic Survey of Persons with Albinism in Nigeria, 2018 – The Albino Foundation. Udeh , N.N., Eze , B.I., Onwubiko , S.N. et al. Prevalence and Profile of Ophthalmic Disorders in Oculocutaneous Albinism: A Field Report from South-Eastern Nigeria. J Community Health 39, 1193–1199 (2014). https://doi.org/10.1007/s10900-014-9878-y. American Academy of Ophthalmology (AAO), Paediatric Ophthalmology, 2019-2020. JJ Kanski. Clinical Ophthalmology. A Systematic Approach. Eighth Edition Elsevier Butterworth Heinemann. London 2008. Duane’s Ophthalmology solution , 2007 Ocular features of Albinism, Eyewiki . Ocular features of Albinism, Medscape.