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Leber congenital amaurosis 15(LCA15)

MedGen UID:
462556
Concept ID:
C3151206
Disease or Syndrome
Synonyms: LCA15; TULP1-Related Leber Congenital Amaurosis
 
Gene (location): TULP1 (6p21.31)
 
Monarch Initiative: MONDO:0013457
OMIM®: 613843

Definition

Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis, whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (summary by Gu et al., 1997). Mutation in TULP1 can also cause a form of autosomal recessive retinitis pigmentosa (RP14; 600132). For a general phenotypic description and a discussion of the genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000. [from OMIM]

Additional description

From MedlinePlus Genetics
At least 20 genetic types of Leber congenital amaurosis have been described. The types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities.

In very rare cases, delayed development and intellectual disability have been reported in people with the features of Leber congenital amaurosis. Because of the visual loss, affected children may become isolated. Providing children with opportunities to play, hear, touch, understand and other early educational interventions may prevent developmental delays in children with Leber congenital amaurosis.

A specific behavior called Franceschetti's oculo-digital sign is characteristic of Leber congenital amaurosis. This sign consists of affected individuals poking, pressing, and rubbing their eyes with a knuckle or finger. Poking their eyes often results in the sensation of flashes of light called phosphenes. Researchers suspect that this behavior may contribute to deep-set eyes in affected children.

Leber congenital amaurosis is also associated with other vision problems, including an increased sensitivity to light (photophobia), involuntary movements of the eyes (nystagmus), and extreme farsightedness (hyperopia). The pupils, which usually expand and contract in response to the amount of light entering the eye, do not react normally to light. Instead, they expand and contract more slowly than normal, or they may not respond to light at all.

Leber congenital amaurosis, also known as LCA, is an eye disorder that is present from birth (congenital). This condition primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. The visual impairment tends to be severe and may worsen over time.  https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis

Clinical features

From HPO
Photophobia
MedGen UID:
43220
Concept ID:
C0085636
Sign or Symptom
Excessive sensitivity to light with the sensation of discomfort or pain in the eyes due to exposure to bright light.
Eye poking
MedGen UID:
115926
Concept ID:
C0233593
Mental or Behavioral Dysfunction
Repetitive pressing, poking, and/or rubbing in the eyes.
Hemeralopia
MedGen UID:
42391
Concept ID:
C0018975
Disease or Syndrome
A visual defect characterized by the inability to see as clearly in bright light as in dim light. The word hemeralopia literally means day blindness.
Hypermetropia
MedGen UID:
43780
Concept ID:
C0020490
Disease or Syndrome
An abnormality of refraction characterized by the ability to see objects in the distance clearly, while objects nearby appear blurry.
Myopia
MedGen UID:
44558
Concept ID:
C0027092
Disease or Syndrome
Nearsightedness, also known as myopia, is an eye condition that causes blurry distance vision. People who are nearsighted have more trouble seeing things that are far away (such as when driving) than things that are close up (such as when reading or using a computer). If it is not treated with corrective lenses or surgery, nearsightedness can lead to squinting, eyestrain, headaches, and significant visual impairment.\n\nNearsightedness usually begins in childhood or adolescence. It tends to worsen with age until adulthood, when it may stop getting worse (stabilize). In some people, nearsightedness improves in later adulthood.\n\nFor normal vision, light passes through the clear cornea at the front of the eye and is focused by the lens onto the surface of the retina, which is the lining of the back of the eye that contains light-sensing cells. People who are nearsighted typically have eyeballs that are too long from front to back. As a result, light entering the eye is focused too far forward, in front of the retina instead of on its surface. It is this change that causes distant objects to appear blurry. The longer the eyeball is, the farther forward light rays will be focused and the more severely nearsighted a person will be.\n\nNearsightedness is measured by how powerful a lens must be to correct it. The standard unit of lens power is called a diopter. Negative (minus) powered lenses are used to correct nearsightedness. The more severe a person's nearsightedness, the larger the number of diopters required for correction. In an individual with nearsightedness, one eye may be more nearsighted than the other.\n\nEye doctors often refer to nearsightedness less than -5 or -6 diopters as "common myopia." Nearsightedness of -6 diopters or more is commonly called "high myopia." This distinction is important because high myopia increases a person's risk of developing other eye problems that can lead to permanent vision loss or blindness. These problems include tearing and detachment of the retina, clouding of the lens (cataract), and an eye disease called glaucoma that is usually related to increased pressure within the eye. The risk of these other eye problems increases with the severity of the nearsightedness. The term "pathological myopia" is used to describe cases in which high myopia leads to tissue damage within the eye.
Night blindness
MedGen UID:
10349
Concept ID:
C0028077
Disease or Syndrome
Inability to see well at night or in poor light.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells.
Color vision defect
MedGen UID:
115964
Concept ID:
C0234629
Finding
An anomaly in the ability to discriminate between or recognize colors.
Reduced visual acuity
MedGen UID:
65889
Concept ID:
C0234632
Finding
Diminished clarity of vision.
Constriction of peripheral visual field
MedGen UID:
68613
Concept ID:
C0235095
Finding
An absolute or relative decrease in retinal sensitivity extending from edge (periphery) of the visual field in a concentric pattern. The visual field is the area that is perceived simultaneously by a fixating eye.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disc (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.
Posterior subcapsular cataract
MedGen UID:
163646
Concept ID:
C0858617
Acquired Abnormality
A type of cataract affecting the posterior pole of lens immediately adjacent to ('beneath') the Lens capsule.
Peripapillary atrophy
MedGen UID:
473480
Concept ID:
C1719838
Pathologic Function
Thinning in the layers of the retina and retinal pigment epithelium around the optic nerve.
Impaired smooth pursuit
MedGen UID:
325176
Concept ID:
C1837458
Finding
An impairment of the ability to track objects with the ocular smooth pursuit system, a class of rather slow eye movements that minimizes retinal target motion.
Attenuation of retinal blood vessels
MedGen UID:
480605
Concept ID:
C3278975
Finding
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.
Slow pupillary light response
MedGen UID:
868184
Concept ID:
C4022576
Finding
Reduced velocity and acceleration in the pupillary light response.
Pigmentary retinopathy
MedGen UID:
1643295
Concept ID:
C4551715
Disease or Syndrome
An abnormality of the retina characterized by pigment deposition. It is typically associated with migration and proliferation of macrophages or retinal pigment epithelial cells into the retina; melanin from these cells causes the pigmentary changes. Pigmentary retinopathy is a common final pathway of many retinal conditions and is often associated with visual loss.
Dull foveal reflex
MedGen UID:
1815097
Concept ID:
C5706191
Finding
Reduced brightness of the foveal reflex, which normally is a bright pinpoint of light that is observed to move sideways or up and down in response to movement of the opthalmoscope.

Professional guidelines

PubMed

Leinonen H, Zhang J, Occelli LM, Seemab U, Choi EH, L P Marinho LF, Querubin J, Kolesnikov AV, Galinska A, Kordecka K, Hoang T, Lewandowski D, Lee TT, Einstein EE, Einstein DE, Dong Z, Kiser PD, Blackshaw S, Kefalov VJ, Tabaka M, Foik A, Petersen-Jones SM, Palczewski K
Nat Commun 2024 Jul 15;15(1):5943. doi: 10.1038/s41467-024-50033-5. PMID: 39009597Free PMC Article
Deng C, Zhao PY, Branham K, Schlegel D, Fahim AT, Jayasundera TK, Khan N, Besirli CG
Graefes Arch Clin Exp Ophthalmol 2022 May;260(5):1543-1550. Epub 2022 Jan 10 doi: 10.1007/s00417-021-05508-2. PMID: 35001204Free PMC Article
Chung DC, Traboulsi EI
J AAPOS 2009 Dec;13(6):587-92. doi: 10.1016/j.jaapos.2009.10.004. PMID: 20006823

Recent clinical studies

Etiology

Rodriguez-Martinez AC, Higgins BE, Tailor-Hamblin V, Malka S, Cheloni R, Collins AM, Bladen J, Henderson R, Moosajee M
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Daich Varela M, Georgiou M, Alswaiti Y, Kabbani J, Fujinami K, Fujinami-Yokokawa Y, Khoda S, Mahroo OA, Robson AG, Webster AR, AlTalbishi A, Michaelides M
Am J Ophthalmol 2023 Feb;246:107-121. Epub 2022 Sep 12 doi: 10.1016/j.ajo.2022.09.002. PMID: 36099972Free PMC Article
Tay SA, Vincent AL
Ophthalmic Genet 2020 Aug;41(4):354-357. Epub 2020 May 20 doi: 10.1080/13816810.2020.1766086. PMID: 32432520
Stunkel M, Bhattarai S, Kemerley A, Stone EM, Wang K, Mullins RF, Drack AV
Ophthalmology 2015 Jan;122(1):192-9. Epub 2014 Sep 10 doi: 10.1016/j.ophtha.2014.07.037. PMID: 25217415Free PMC Article
Ferrucci S, Anderson SF, Townsend JC
Optom Vis Sci 1998 Aug;75(8):560-70. doi: 10.1097/00006324-199808000-00021. PMID: 9734800

Diagnosis

Daich Varela M, Georgiou M, Alswaiti Y, Kabbani J, Fujinami K, Fujinami-Yokokawa Y, Khoda S, Mahroo OA, Robson AG, Webster AR, AlTalbishi A, Michaelides M
Am J Ophthalmol 2023 Feb;246:107-121. Epub 2022 Sep 12 doi: 10.1016/j.ajo.2022.09.002. PMID: 36099972Free PMC Article
Tay SA, Vincent AL
Ophthalmic Genet 2020 Aug;41(4):354-357. Epub 2020 May 20 doi: 10.1080/13816810.2020.1766086. PMID: 32432520
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Stunkel M, Bhattarai S, Kemerley A, Stone EM, Wang K, Mullins RF, Drack AV
Ophthalmology 2015 Jan;122(1):192-9. Epub 2014 Sep 10 doi: 10.1016/j.ophtha.2014.07.037. PMID: 25217415Free PMC Article

Therapy

Bommakanti N, Young BK, Sisk RA, Berrocal AM, Duncan JL, Bakall B, Mathias MT, Ahmed I, Chorfi S, Comander J, Nagiel A, Besirli CG
Ophthalmol Retina 2024 Jan;8(1):42-48. Epub 2023 Sep 3 doi: 10.1016/j.oret.2023.08.017. PMID: 37660736Free PMC Article
Cideciyan AV, Aguirre GK, Jacobson SG, Butt OH, Schwartz SB, Swider M, Roman AJ, Sadigh S, Hauswirth WW
Invest Ophthalmol Vis Sci 2014 Dec 23;56(1):526-37. doi: 10.1167/iovs.14-15895. PMID: 25537204Free PMC Article
Jacobson SG, Cideciyan AV, Ratnakaram R, Heon E, Schwartz SB, Roman AJ, Peden MC, Aleman TS, Boye SL, Sumaroka A, Conlon TJ, Calcedo R, Pang JJ, Erger KE, Olivares MB, Mullins CL, Swider M, Kaushal S, Feuer WJ, Iannaccone A, Fishman GA, Stone EM, Byrne BJ, Hauswirth WW
Arch Ophthalmol 2012 Jan;130(1):9-24. Epub 2011 Sep 12 doi: 10.1001/archophthalmol.2011.298. PMID: 21911650Free PMC Article
Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, Rossi S, Marshall K, Banfi S, Surace EM, Sun J, Redmond TM, Zhu X, Shindler KS, Ying GS, Ziviello C, Acerra C, Wright JF, McDonnell JW, High KA, Bennett J, Auricchio A
Mol Ther 2010 Mar;18(3):643-50. Epub 2009 Dec 1 doi: 10.1038/mt.2009.277. PMID: 19953081Free PMC Article
Ferrucci S, Anderson SF, Townsend JC
Optom Vis Sci 1998 Aug;75(8):560-70. doi: 10.1097/00006324-199808000-00021. PMID: 9734800

Prognosis

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BMC Med Genomics 2021 Mar 10;14(1):74. doi: 10.1186/s12920-021-00874-6. PMID: 33691693Free PMC Article
Tay SA, Vincent AL
Ophthalmic Genet 2020 Aug;41(4):354-357. Epub 2020 May 20 doi: 10.1080/13816810.2020.1766086. PMID: 32432520
Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, Rossi S, Marshall K, Banfi S, Surace EM, Sun J, Redmond TM, Zhu X, Shindler KS, Ying GS, Ziviello C, Acerra C, Wright JF, McDonnell JW, High KA, Bennett J, Auricchio A
Mol Ther 2010 Mar;18(3):643-50. Epub 2009 Dec 1 doi: 10.1038/mt.2009.277. PMID: 19953081Free PMC Article
Ferrucci S, Anderson SF, Townsend JC
Optom Vis Sci 1998 Aug;75(8):560-70. doi: 10.1097/00006324-199808000-00021. PMID: 9734800

Clinical prediction guides

Rodriguez-Martinez AC, Higgins BE, Tailor-Hamblin V, Malka S, Cheloni R, Collins AM, Bladen J, Henderson R, Moosajee M
Int J Mol Sci 2023 Sep 11;24(18) doi: 10.3390/ijms241813932. PMID: 37762234Free PMC Article
Ma DJ, Lee HS, Kim K, Choi S, Jang I, Cho SH, Yoon CK, Lee EK, Yu HG
BMC Med Genomics 2021 Mar 10;14(1):74. doi: 10.1186/s12920-021-00874-6. PMID: 33691693Free PMC Article
Zou X, Fu Q, Fang S, Li H, Ge Z, Yang L, Xu M, Sun Z, Li H, Li Y, Dong F, Chen R, Sui R
Retina 2019 Oct;39(10):2040-2052. doi: 10.1097/IAE.0000000000002242. PMID: 30134391
Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, Rossi S, Marshall K, Banfi S, Surace EM, Sun J, Redmond TM, Zhu X, Shindler KS, Ying GS, Ziviello C, Acerra C, Wright JF, McDonnell JW, High KA, Bennett J, Auricchio A
Mol Ther 2010 Mar;18(3):643-50. Epub 2009 Dec 1 doi: 10.1038/mt.2009.277. PMID: 19953081Free PMC Article
Richard M, Roepman R, Aartsen WM, van Rossum AG, den Hollander AI, Knust E, Wijnholds J, Cremers FP
Hum Mol Genet 2006 Oct 15;15 Spec No 2:R235-43. doi: 10.1093/hmg/ddl195. PMID: 16987889

Recent systematic reviews

Burgess FR, Hall HN, Megaw R
Asia Pac J Ophthalmol (Phila) 2022 Jul-Aug 01;11(4):380-391. Epub 2022 Aug 30 doi: 10.1097/APO.0000000000000545. PMID: 36041151
Wang X, Yu C, Tzekov RT, Zhu Y, Li W
Orphanet J Rare Dis 2020 Feb 14;15(1):49. doi: 10.1186/s13023-020-1304-1. PMID: 32059734Free PMC Article

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