Years published: 2023
NORD gratefully acknowledges Madison Webster, MD Candidate, Creighton School of Medicine and Paul Rychwalski, MD, Chief of Ophthalmology at Children’s Hospital & Medical Center, Omaha, NE for the preparation of this report.
Ocular albinism with late onset sensorineural deafness (OASD) is a rare inherited subtype of ocular albinism.
It is characterized by vision abnormalities, translucent blue eye color and moderate to severe deafness. Similar to ocular albinism, vision impairment is present at birth and remains stable throughout life. However, hearing difficulty arises later in life from adolescence to the fourth or fifth decade.
This condition is thought to be caused by changes (pathogenic variants or mutations) in the GPR143 gene (also known as the OA1 gene) or by variants in other genes located in the same region of the X chromosome. OASD is inherited in an X-linked pattern.
The main symptoms include ocular albinism and deafness. Albinism refers to lack of melanin synthesis, or the pigment of skin, eyes and hair.
In ocular albinism, only the eyes (iris, retina) are affected, not the skin or hair. This leads to translucent blue eyes and other vision abnormalities. In the back of the eye, there is a layer called the retina, which is made up of photoreceptor cells responsible for capturing light and transmitting it into electrical and chemical signals for the brain to interpret into an image. In ocular albinism, this retina layer lacks pigment which leads to hypersensitivity to light (photophobia) and an abnormal connection between the retina and the optic nerve that travels to the brain.
There are two types of deafness, sensorineural and conductive. Conductive deafness refers to blockage of the outer or middle ear in which sound cannot efficiently pass through to the inner ear, whereas sensorineural deafness refers to the hearing loss in the inner ear, usually affecting the nerves of the cochlea (spiral-shaped cavity).
The signs and symptoms of OSAD reported in the medical literature include:
· Eye and vision abnormalities due to the abnormal connection between the retina and the optic nerve such as crossed eyes (strabismus), rapid involuntary eye movements (nystagmus) and blurred vision (decreased visual acuity)
· Sensorineural deafness beginning in adolescence to the fourth or fifth decade of life
There is no consensus regarding the true cause of OASD, but it is likely closely tied to the cause of ocular albinism type 1 (OA1).
OA1 is an X-linked recessive disorder; hence, the gene associated with the disorder is located on the X chromosome. Genes are bits of DNA that code for specific proteins that our bodies need to function. OASD is thought to be caused by changes (pathogenic variants or mutations) in the GPR143 gene, also known as the OA1 gene. GPR stands for G protein-coupled receptor, the protein product that is produced from the GPR143 gene. This receptor is bound to the membrane of melanosomes, a specialized cellular structure which functions to synthesize and store melanin (pigment). The G protein-coupled receptor acts as a signaling molecule to trigger growth and development of these melanosomes to effectively produce melanin. Melanin is the substance that gives the eye color and plays a role in normal vision in the retina. When a disease-causing variant in the OA1 gene is present, melanosomes cannot carry out their role and no pigment is produced.
There are a few specific variants in the GPR143 gene that are known to be associated with OASD. Some patients with OASD may have variations in several different areas of the gene that lead to the same medical problems.
Since OASD is a subtype of OA1, there is overlap in the cause of these disorders. A study of a South African family with OASD found that there was a tight linkage between a DXS452 genetic variant in the same region on the X chromosome seen in OA1 (Winship et al.). One possible explanation of this finding is that OA1 and OASD are caused by different forms of a gene at the same location on the X chromosome. Therefore, a small variation in the Xp22.3 region could lead to OASD or OA1. Another explanation is that OASD and OA1 have contiguous gene defects, meaning the gene associated with OASD is physically close to the OA1 gene.
Although OASD likely results from variants in genes in the Xp22.3 region, in some patients, other genes may be involved. One study reported a patient with a small deletion in the TBL1 gene, which is located close to the OA1 gene (Bassi et al.). This study showed that there could be a small deletion that removes a portion of both the GPR143 and TBL1 genes leading to OASD. Variants in the neighboring SHROOM2 gene have also been described. These findings may help explain why hearing loss occurs in patients with characteristics of ocular albinism.
OASD is inherited in an X-linked recessive manner. X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder can reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
It is estimated that fewer than 1,000 people in the U.S. have OASD. Since the disorder follows an X-linked recessive inheritance pattern, more males are affected than females.
Diagnosis is often suspected early in life based on lack of color (hypopigmentation) of the eyes, vision abnormalities and family history. Diagnostic testing typically involves working with a geneticist and doing adequate molecular testing to identify the variants in the GPR143 gene that are known to be associated with OASD. Molecular genetic tests can be used to analyze entire gene coding sequences and areas of gene deletion or duplication. Family history information can be useful to look for an X-linked inheritance pattern.
Regarding late onset sensorineural deafness, an audiometry test is recommended in the fourth decade of life. This test evaluates the sensitivity of an individual’s hearing. Physical examinations such as otoscopic examination (visualization of eardrum) will likely be normal as the patient typically develops sensorineural hearing loss without any structural abnormalities.
There are no definitive treatments for OASD, but several actions can be taken to lessen symptoms.
Annual eye exams with an ophthalmologist are recommended for patients under the age of 16, and every 2-3 years after 16. Refractive errors (vision problem) are treated with corrective glasses. Tinted lenses can be added for patients with light sensitivity (photophobia).
If a patient has crossed eyes (strabismus), surgery or patching can be done. Surgery helps to physically realign the muscles around the eye (extraocular eye muscles), whereas patching is a noninvasive way of correcting alignment by strengthening the weak ocular muscles.
Depending on the severity of hearing loss and how rapid the deterioration is, hearing aids may be used to amplify sound and cochlear implants can be considered to electrically stimulate the auditory nerve.
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Oetting WS. New insights into ocular albinism type 1 (OA1): Mutations and polymorphisms of the OA1 gene. Hum Mutat. 2002;19(2):85-92. doi:10.1002/humu.10034
Bassi MT, Ramesar RS, Caciotti B, et al. X-linked late-onset sensorineural deafness caused by a deletion involving OA1 and a novel gene containing WD-40 repeats. Am J Hum Genet. 1999;64(6):1604-1616. doi:10.1086/302408
Winship IM, Babaya M, Ramesar RS. X-linked ocular albinism and sensorineural deafness: linkage to Xp22.3. Genomics. 1993;18(2):444-445. doi:10.1006/geno.1993.1495
Lewis RA. Ocular Albinism, X-Linked – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2004 Mar 12 [updated 2015 Nov 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023. PMID: 20301517.
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