Ocular albinism late onset sensorineural deafness

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Ocular albinism late onset sensorineural deafness

Ocular albinism late onset sensorineural deafness (OASD) is a rare, X-linked recessive disease characterized by intense visual impairments, reduced retinal pigments, translucent pale-blue irises and moderately severe hearing loss from adolescence to middle-age. [1] It is a subtype of Ocular Albinism (OA) that is linked to Ocular albinism type I (OA1). OA1 is the most common form of ocular albinism, affecting at least 1/60,000 males.

Contents

OA has two patterns of inheritance: X-linked and autosomal. X-linked OA includes OA1 (Nettleship-Falls type), OA2 (Forsius-Eriksson type) and OASD. Autosomal inheritance, on the other hand, includes OCA3 (autosomal recessive OA) and OA with sensorineural deafness. [2] As OA1 is X-linked, males are generally more affected than females. The cause of OASD is believed to involve mutations of the GPR143 gene, which is responsible for pigment proteins production and melanosome growth control. This gene is located on the X-chromosome at Xp22.3, which is also where TBL1 gene is found. The physical proximity of the two genes suggest that OASD and OA1 result from contiguous-gene syndrome.

There are three main diagnostic methods: molecular genetic tests, family pedigree analysis and antenatal diagnosis. While there is no definite treatment for OASD, annual ophthalmologic examinations are suggested for preventative measures.

Signs and Symptoms

The main signs and symptoms (phenotypes) of OASD, shown in different parts of the body, include the following: [3] [4]

Although symptoms vary between individuals, the signs and symptoms mentioned above all have the Human Phenotype Ontology (HPO) frequency of 90% and are categorized as "very frequent (80-99%)". [3] Strabismus, leading to squint eyes, and cross-eyed individuals, are shown by 30-79% of people who have OASD. [3] The HPO has collected information on symptoms demonstrated in medical resources. The HPO ID helps access more information about the symptom.[ citation needed ]

However, there are additional possible signs and symptoms of OASD that are not listed by HPO such as the following: [3]

Associated conditions

This image shows an otoscopic examination being carried on a patient. Slit lamp Eye examination by Ophthalmologist.jpg
This image shows an otoscopic examination being carried on a patient.

OASD is one of the many contiguous gene syndromes related to OA1. Contiguous gene syndromes are due to the deletion or duplication of a group of genes physically clustered together. [5] Many patients with contiguous gene syndromes that involves the OA1 gene being deleted in the Xp22.3 region have been described to have albino phenotypes.[ citation needed ]

Some of the other conditions of close linkage to type I ocular albinism are of the following: [6]  

Causes

Genetic mutations

OA is a recessive X-linked disorder; hence, the disorder is located on the X chromosome. It is mainly due to mutations in the GPR143 gene(OA1), located at Xp22.3; this gene gives instructions for the production of protein involved in pigmentation of the eyes and skin. [1] It helps control the growth of melanosomes, which are cellular structures that produce and store a pigment called melanin. Melanin is the substance that gives skin, hair, and eyes their color; it also plays a role in normal vision in the retina. [1]

G protein-coupled receptor (GPCR)

A G protein-coupled receptor, which is the protein product, is localized on the membrane of melanosomes in pigmented cells in the eye.  There is an identical gene mutated for congenital nystagmus 6 (OMIM code: 300814). Although OASD results from mutations in the Xp22.3 region, it may vary depending on individuals. Some may have additional mutations (usually microdeletions) in the contiguous genes TBL1X and SHROOM2. [7] Mutations in GNA13 (17q24.1), activated by OA1, have also been reported to cause the ocular albinism phenotype. [7] These genetic changes can stop the protein from reaching melanosomes to control their growth, or the protein's function is disrupted although the protein reaches melanosomes successfully. Consequently, melanosomes in both the skin cells and retina enlarge abnormally. Researchers have ambiguous interpretations on how these macromelanosomes have correlation to vision loss and other eye abnormalities in patients suffering ocular albinism. [7]

Other

While OASD is largely due to mutations, another possible cause is contiguous gene defects that include OA1 gene. Due to the presence of several forms of X-linked hearing loss, the gene responsible for sensorineural deafness could also map to the same region. [8]

Pathogenesis

OASD belongs in the subtype of OA1 and thus has similar pathogenesis with OA1. The physical proximity of genes related to OASD (GPR143 gene and TBL1 gene) made researchers postulate that OASD and OA1 are the result of a contiguous-gene syndrome. [9] [10] In other words, OASD may be explained by gene pleiotropy of OA1; hence, OA1 and OASD are two separate, yet commonly associated entities.[ citation needed ]

GPR143 Gene

Surace et al.(2000) conducted animal studies on CD1 albino female mice to investigate the pathogenesis of OA1. [11] They found that the expression of OA1 gene (GPR143 gene) is observed to be stronger after birth and is maintained until adulthood. Nevertheless, a decrease is observed after adulthood. This finding suggests that OA1 gene expression is controlled by transcription factors that play crucial roles in the formation and pigmentation of melanosomes. [11]

Abnormal Growth of Melanosomes

Incerti et al. (2000) attempt to better understand the pathogenesis of OA1 using knockout mice with inactivated OA1 genes. [12]  OA1 gene was made inactive with gene targeting technique. Ultrastructural analysis was performed on the melanosomes found in the retinal pigment epithelium (RPE) in both normal and knockout mice. Only normal-sized melanosomes were found in the wild-type controls. In knockout mice, on the other hand, abnormally large melanosomes were also found in addition to the normal-sized melanosomes. However, no melanosomes of intermediate sizes were observed. [12]

Moreover, a single core region within the giant pigmented melanosome that resembles the structure of a normal membrane-free melanosome was identified. Together, the evidence suggest that the formation of macromelanosomes is due to the abnormal growth of individual melanosomes, rather than the fusion of multiple melanosomes. This disagrees with the previous model on macromelanosomes formation. It stated that the separation failure of pre-melanosomes from the endoplasmic reticulum, accumulating structural proteins and enzymes, caused progressive organelle distension. The present theory suggests that the normal melanosomes and macromelanosomes have similar pathways of formation and maturation processes. [12] This offered new insight into the pathogenesis as OA1 gene appears to have a crucial role in the final stages of melanosome development and maturation. Eye examination of the adult knockout mice revealed significantly lighter coloured pigmented in the RPE than the normal control mice. [12]

TBL1 Gene

OA1 gene is not the only gene involved in the pathogenesis of OASD. TBL1 gene is also identified to affect the hearing phenotype of OASD. TBL1 is located in the Xp22.3 loci which is of close proximity to the OA1 gene, on the telomeric side outside its critical region. [10] Genomic analysis by Bassi et al.(1999) found that this gene is either partially or completely deleted in patients carrying the Xp22.3 terminal deletions. [10] One patient with deletions of both TBL1 gene and OA1 gene displayed OA1 phenotype as well as associated late-onset sensorineural deafness. [10] Hence, it could be inferred that TBL1 gene is involved in the pathogenesis of OASD.[ citation needed ]

Unusual Optic Pathways

Furthermore, in the mutant mice with inactivated OA1 gene, the size of the uncrossed optic pathways was reduced in favour of the cross pathways. The retinofugal pathway, projecting from the eye towards the brain, of the knockout mice also displayed a misrouting of optic fibres. [11] [12] Such misrouting led to the loss of stereoscopic vision in patients with ocular albinism. [12] The mutant mice also had a significantly smaller mean ipsilateral volume of terminal label in their lateral geniculate nucleus (LGN) than the normal control mice, as shown with the Mann-Whitney test at 5% significance level. Yet, this difference is independent of the LGN volume as the size of the nucleus was comparable in both groups. [12]  However, the absence of macromelanosome in the chiasmic region, where the final retinal axon enters, illustrates that there is no direct causation between the formation of macromelanosomes and abnormalities in the optic pathways. [12]

Diagnosis

There are three main types of diagnosis methods: [13]

  1. Molecular genetic tests are composed of sequence analyses of the entire coding region and deletion/duplication analysis. GPR143 gene mutation is found in most affected males.
  2. Family pedigree analysis [14]
  3. Antenatal diagnosis: Prenatal testing can be used when women are known carriers of the GPR143 gene mutation, using chorionic villus sampling or amniocentesis. Preimplantation genetic diagnosis may be available. As an alternative, the expression of OA1 has been reported to be detected exclusively after birth.
Family pedigree diagnosed with OA1, showing different phenotypes. Family pedigree.png
Family pedigree diagnosed with OA1, showing different phenotypes.

Female obligate carriers have patchy streaks of pigment in the mid-peripheral retina (pigmentary mosaicism), which demonstrates random X inactivation. Those with more advanced ocular manifestations due to skewed X-inactivation have reported reduced visual acuity and nystagmus. [15] Despite the fact that melanin macro-globules are not pathognomonic, they are commonly seen during skin biopsy. [16]

As patients with OASD demonstrate severe hearing loss in their fourth or fifth decade of life, an audiometry test is recommended in the fourth decade. Physical examinations such as otoscopic examination may give uncertain results as the patient may have hearing loss in spite of having no structural abnormalities. [2]

Treatment

There is no definite treatment for the cure of OASD. Thus, annual ophthalmologic examinations are advised for patients below the age of 16, and every 2–3 years above 16. [17] Treatments are targeted towards specific symptoms. Refractive problems are dealt with by the use of corrective glasses with tinted lenses for those with photophobia. Additional low vision aids and special education may be needed. Extraocular muscle surgery can help restore peripheral visual fusion fields for eye alignment and improve head posture; this helps relieve strabismus and nystagmus. [7] [18]

Related Research Articles

<span class="mw-page-title-main">Albinism in humans</span> Condition characterized by absence of pigment

Albinism is a congenital condition characterized in humans by the partial or complete absence of pigment in the skin, hair and eyes. Albinism is associated with a number of vision defects, such as photophobia, nystagmus, and amblyopia. Lack of skin pigmentation makes for more susceptibility to sunburn and skin cancers. In rare cases such as Chédiak–Higashi syndrome, albinism may be associated with deficiencies in the transportation of melanin granules. This also affects essential granules present in immune cells, leading to increased susceptibility to infection.

<span class="mw-page-title-main">Tietz syndrome</span> Congenital disorder

Tietz syndrome, also called Tietz albinism-deafness syndrome or albinism and deafness of Tietz, is an autosomal dominant congenital disorder characterized by deafness and leucism. It is caused by a mutation in the microphthalmia-associated transcription factor (MITF) gene. Tietz syndrome was first described in 1963 by Walter Tietz (1927–2003) a German Physician working in California.

<span class="mw-page-title-main">Retinitis pigmentosa</span> Gradual retinal degeneration leading to progressive sight loss

Retinitis pigmentosa (RP) is a member of a group of genetic disorders called inherited retinal dystrophy (IRD) that cause loss of vision. Symptoms include trouble seeing at night and decreasing peripheral vision. As peripheral vision worsens, people may experience "tunnel vision". Complete blindness is uncommon. Onset of symptoms is generally gradual and often begins in childhood.

<span class="mw-page-title-main">Wolfram syndrome</span> Human disease

Wolfram syndrome, also called DIDMOAD, is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders including neurodegeneration. Symptoms can start to appear as early as childhood to adult years. There is a 25% recurrence risk in children.

<span class="mw-page-title-main">Waardenburg syndrome</span> Genetic condition involving hearing loss and depigmentation

Waardenburg syndrome is a group of rare genetic conditions characterised by at least some degree of congenital hearing loss and pigmentation deficiencies, which can include bright blue eyes, a white forelock or patches of light skin. These basic features constitute type 2 of the condition; in type 1, there is also a wider gap between the inner corners of the eyes called telecanthus, or dystopia canthorum. In type 3, which is rare, the arms and hands are also malformed, with permanent finger contractures or fused fingers, while in type 4, the person also has Hirschsprung's disease. There also exist at least two types that can result in central nervous system (CNS) symptoms such as developmental delay and muscle tone abnormalities.

<span class="mw-page-title-main">Aniridia</span> Absence of the iris, usually involving both eyes

Aniridia is the absence of the iris, a muscular structure that opens and closes the pupil to allow light into the eye. It is also responsible for eye color. Without it, the central eye appears all black. It can be congenital, in which both eyes are usually involved, or caused by a penetrant injury. Isolated aniridia is a congenital disorder that is not limited to a defect in iris development, but is a panocular condition with macular and optic nerve hypoplasia, cataract, and corneal changes. Vision may be severely compromised and the disorder is frequently associated with some ocular complications: nystagmus, amblyopia, buphthalmos, and cataract. Aniridia in some individuals occurs as part of a syndrome, such as WAGR syndrome, or Gillespie syndrome.

<span class="mw-page-title-main">X-linked recessive inheritance</span> Mode of inheritance

X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males and in females who are homozygous for the gene mutation, see zygosity. Females with one copy of the mutated gene are carriers.

Albinism-black lock-cell migration disorder is the initialism for the following terms and concepts that describe a condition affecting a person's physical appearance and physiology: (1) A – albinism, (2) B – black lock of hair, (3) C – cell migration disorder of the neurocytes of the gut, and (4) D – sensorineural deafness. The syndrome is caused by mutation in the endothelin B receptor gene (EDNRB).

<span class="mw-page-title-main">Hermansky–Pudlak syndrome</span> Medical condition

Heřmanský–Pudlák syndrome is an extremely rare autosomal recessive disorder which results in oculocutaneous albinism, bleeding problems due to a platelet abnormality, and storage of an abnormal fat-protein compound. It is thought to affect around 1 in 500,000 people worldwide, with a significantly higher occurrence in Puerto Ricans, with a prevalence of 1 in 1800. Many of the clinical research studies on the disease have been conducted in Puerto Rico.

<span class="mw-page-title-main">Macular hypoplasia</span> Medical condition

Macular hypoplasia is a rare medical condition involving the underdevelopment of the macula, a small area on the retina responsible for seeing in detail and sensing light. Macular hypoplasia is often associated with albinism.

Mitochondrially encoded tRNA histidine, also known as MT-TH, is a transfer RNA which, in humans, is encoded by the mitochondrial MT-TH gene.

<span class="mw-page-title-main">GPR143</span> Protein-coding gene in the species Homo sapiens

G-protein coupled receptor 143, also known as Ocular albinism type 1 (OA1) in humans, is a conserved integral membrane protein with seven transmembrane domains and similarities with G protein-coupled receptors (GPCRs) that is expressed in the eye and epidermal melanocytes. This protein encoded by the GPR143 gene, whose variants can lead to Ocular albinism type 1.

<span class="mw-page-title-main">CLCN4</span> Protein-coding gene in humans

H(+)/Cl(-) exchange transporter 4 is a protein that in humans is encoded by the CLCN4 gene.

<span class="mw-page-title-main">TBL1X</span> Protein-coding gene in the species Homo sapiens

Transducin (beta)-like 1X-linked, also known as TBL1X, is a protein which in humans is encoded by the TBL1X gene.

Ocular albinism is a form of albinism which, in contrast to oculocutaneous albinism, presents primarily in the eyes. There are multiple forms of ocular albinism, which are clinically similar.

Oculocutaneous albinism type I or type 1A is form of the autosomal recessive condition oculocutaneous albinism that is caused by a dysfunction in the gene for tyrosinase.

<span class="mw-page-title-main">Ocular albinism type 1</span> Most common type of ocular albinism

Ocular albinism type 1(OA1) is the most common type of ocular albinism, with a prevalence rate of 1:50,000. It is an inheritable classical Mendelian type X-linked recessive disorder wherein the retinal pigment epithelium lacks pigment while hair and skin appear normal. Since it is usually an X-linked disorder, it occurs mostly in males, while females are carriers unless they are homozygous. About 60 missense and nonsense mutations, insertions, and deletions have been identified in Oa1. Mutations in OA1 have been linked to defective glycosylation and thus improper intracellular transportation.

<span class="mw-page-title-main">Vestibulocerebellar syndrome</span> Medical condition

Vestibulocerebellar syndrome, also known as vestibulocerebellar ataxia, is a progressive neurological disorder that causes a variety of medical problems. Initially symptoms present as periodic attacks of abnormal eye movements but may intensify to longer-lasting motor incapacity. The disorder has been localized to the vestibulocerebellum, specifically the flocculonodular lobe. Symptoms of vestibulocerebellar syndrome may appear in early childhood but the full onset of neurological symptoms including nystagmus, ataxia, and tinnitus does not occur until early adulthood. To date, vestibulocerebellar syndrome has only been identified in three families but has affected multiple generations within them. Based on the familial pedigrees it has been characterized as an autosomal dominant disorder, although the exact genetic locus has not been identified. It has been found to be genetically distinct from other seemingly similar forms of neurological syndromes such as episodic ataxia types 1 and 2. Due to its rarity, however, little is known about specific details of the pathology or long-term treatment options. There is currently no cure for vestibulocerebellar syndrome, although some drug therapies have been effective in alleviating particular symptoms of the disorder.

<span class="mw-page-title-main">SERAC1</span> Protein-coding gene in the species Homo sapiens

Serine active site-containing protein 1, or Protein SERAC1 is a protein in humans that is encoded by the SERAC1 gene. The protein encoded by this gene is a phosphatidylglycerol remodeling protein found at the interface of mitochondria and endoplasmic reticula, where it mediates phospholipid exchange. The encoded protein plays a major role in mitochondrial function and intracellular cholesterol trafficking. Defects in this gene are a cause of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL). Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene.

<span class="mw-page-title-main">Nance–Horan syndrome</span> Rare X-linked dominant condition

Nance–Horan syndrome, also known as X-linked congenital cataracts and microcornea, X-linked cataract–dental syndrome, cataracts-oto-dental syndrome, cataract–dental syndrome, and mesiodens–cataract syndrome, is a rare X-linked syndrome characterized by eye and teeth abnormalities, intellectual disability, and facial deformities.

References

  1. 1 2 3 "Ocular albinism: MedlinePlus Genetics". medlineplus.gov. Retrieved 2021-04-01.
  2. 1 2 Tak, Woo-Jung; Kim, Myeung-Nam; Hong, Chang-Kwan; Ro, Byung-In; Song, Kye-Yong; Seo, Seong-Jun (2004-04-06). "Ocular albinism with sensorineural deafness". International Journal of Dermatology. 43 (4): 290–292. doi:10.1111/j.1365-4632.2004.01857.x. ISSN   1365-4632. PMID   15090016. S2CID   20896195.
  3. 1 2 3 4 "Albinism ocular late onset sensorineural deafness | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2021-04-01.
  4. ↑ "Albinism, Ocular, with Late-Onset Sensorineural Deafness disease: Malacards - Research Articles, Drugs, Genes, Clinical Trials". www.malacards.org. Retrieved 2021-04-01.
  5. ↑ Tan, Carmela D.; Rodriguez, E. Rene (2009-01-01), Tubbs, Raymond R.; Stoler, Mark H. (eds.), "Chapter 20 - Molecular Pathology of the Cardiovascular System", Cell and Tissue Based Molecular Pathology, Philadelphia: Churchill Livingstone, pp. 214–240, ISBN   978-0-443-06901-7 , retrieved 2021-04-01
  6. ↑ Carden, Susan M.; Boissy, Raymond E.; Schoettker, Pamela J.; Good, William V. (1998-02-01). "Albinism: modern molecular diagnosis". British Journal of Ophthalmology. 82 (2): 189–195. doi:10.1136/bjo.82.2.189. ISSN   0007-1161. PMC   1722467 . PMID   9613388.
  7. 1 2 3 4 "Albinism, Ocular Type 1 | Hereditary Ocular Diseases". disorders.eyes.arizona.edu. Retrieved 2021-04-01.
  8. ↑ Winship, Ingrid M.; Babaya, Michelle; Ramesar, Rajkumar S. (November 1993). "X-Linked Ocular Albinism and Sensorineural Deafness: Linkage to Xp22.3". Genomics. 18 (2): 444–445. doi:10.1006/geno.1993.1495. PMID   8288253.
  9. ↑ "Albinism - EyeWiki". eyewiki.aao.org. Retrieved 2021-04-01.
  10. 1 2 3 4 Bassi, MT; Ramesar, RS; Caciotti, B; Winship, IM; Grandi, AD; Riboni, M; Townes, PL; Beighton, P; Ballabio, A; Borsani, G (June 1, 1999). "X-Linked Late-Onset Sensorineural Deafness CAused by a Deletion Involving OA1 and a Novel Gene Containing WD-40 Repeats". The American Journal of Human Genetics. 64 (6): 1604–1616. doi:10.1086/302408. PMC   1377903 . PMID   10330347.
  11. 1 2 3 Surace, EM; Angeletti, B; Ballabio, A; Marigo, V (2000-12-01). "Expression Pattern of the Ocular Albinism Type 1 (Oa1) Gene in the Murine Retinal Pigment Epithelium". Investigative Ophthalmology & Visual Science. 41 (13): 4333–4337. ISSN   1552-5783. PMID   11095635.
  12. 1 2 3 4 5 6 7 8 Incerti, B; Cortese, K; Pizzigoni, A; Surace, EM; Varani, S; Coppola, M; Jeffery, G; Seeliger, M; Jaissle, G; Bennett, DC; Marigo, V (2000-11-22). "Oa1 knock-out: new insights on the pathogenesis of ocular albinism type 1". Human Molecular Genetics. 9 (19): 2781–2788. doi:10.1093/hmg/9.19.2781. ISSN   0964-6906. PMID   11092754.
  13. ↑ "Orphanet: X linked recessive ocular albinism". orpha.net. Retrieved 2021-04-01.
  14. ↑ Lang, G. E.; Rott, H.-D.; Pfeiffer, R. A. (1990-01-01). "X-linked ocular albinism". Ophthalmic Paediatrics and Genetics. 11 (4): 265–271. doi:10.3109/13816819009015712. ISSN   0167-6784. PMID   2096354.
  15. ↑ Fabian‐Jessing, BK; Vestergaard, EM; Plomp, AS; Bergen, AA; Dreschler, WA; Duno, M; Winiarska, BS; Neumann, L; Gaihede, M; Vorum, H; Petersen, MB (2018-07-16). "Ocular albinism with infertility and late‐onset sensorineural hearing loss". American Journal of Medical Genetics Part A. 176 (7): 1587–1593. doi:10.1002/ajmg.a.38836. ISSN   1552-4825. PMID   30160833. S2CID   52127432.
  16. ↑ "Ocular albinism with late-onset sensorineural deafness - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-04-01.
  17. ↑ "The routine eye examination ('sight test') - The College of Optometrists". guidance.college-optometrists.org. Retrieved 2021-04-14.
  18. ↑ Lewis, RA (2015-11-19). "Ocular Albinism, X-Linked". Europe PMC. Retrieved 2021-04-15.
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