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Leber congenital amaurosis 4(LCA4)

MedGen UID:
346808
•Concept ID:
C1858386
•
Disease or Syndrome
Synonyms: AIPL1-Related Leber Congenital Amaurosis; Amaurosis congenita of Leber, type 4; LCA4
 
Gene (location): AIPL1 (17p13.2)
 
Monarch Initiative: MONDO:0011458
OMIM®: 604393

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 (LCA), whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (Gu et al., 1997). Various intermediate phenotypes between LCA and retinitis pigmentosa are known and are sometimes described as 'early-onset severe rod-cone dystrophy' or 'early-onset retinal degeneration' (Booij et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000; for cone-rod dystrophy, see 120970. [from OMIM]

Additional description

From MedlinePlus Genetics
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.

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.  https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis

Clinical features

From HPO
Keratoconus
MedGen UID:
44015
•Concept ID:
C0022578
•
Disease or Syndrome
A cone-shaped deformity of the cornea characterized by the presence of corneal distortion secondary to thinning of the apex.
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Night blindness
MedGen UID:
10349
•Concept ID:
C0028077
•
Disease or Syndrome
Inability to see well at night or in poor light.
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Reduced visual acuity
MedGen UID:
65889
•Concept ID:
C0234632
•
Finding
Diminished clarity of vision.
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Pendular nystagmus
MedGen UID:
78770
•Concept ID:
C0271388
•
Disease or Syndrome
Rhythmic, involuntary sinusoidal oscillations of one or both eyes. The waveform of pendular nystagmus may occur in any direction.
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Macular atrophy
MedGen UID:
140841
•Concept ID:
C0423421
•
Finding
Well-demarcated area(s) of partial or complete depigmentation in the macula, reflecting atrophy of the retinal pigment epithelium with associated retinal photoreceptor loss.
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Blindness
MedGen UID:
99138
•Concept ID:
C0456909
•
Disease or Syndrome
Blindness is the condition of lacking visual perception defined as a profound reduction in visual perception. On the 6m visual acuity scale, blindness is defined as less than 3/60. On the 20ft visual acuity scale, blindness is defined as less than 20/400. On the decimal visual acuity scale, blindness is defined as less than 0.05. Blindness is typically characterized by a visual field of no greater than 10 degrees in radius around central fixation.
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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.
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Attenuation of retinal blood vessels
MedGen UID:
480605
•Concept ID:
C3278975
•
Finding
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Undetectable light- and dark-adapted electroretinogram
MedGen UID:
867212
•Concept ID:
C4021570
•
Finding
Absence of the combined rod-and-cone response on electroretinogram.
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Cone-rod dystrophy
MedGen UID:
896366
•Concept ID:
C4085590
•
Disease or Syndrome
The first signs and symptoms of cone-rod dystrophy, which often occur in childhood, are usually decreased sharpness of vision (visual acuity) and increased sensitivity to light (photophobia). These features are typically followed by impaired color vision (dyschromatopsia), blind spots (scotomas) in the center of the visual field, and partial side (peripheral) vision loss. Over time, affected individuals develop night blindness and a worsening of their peripheral vision, which can limit independent mobility. Decreasing visual acuity makes reading increasingly difficult and most affected individuals are legally blind by mid-adulthood. As the condition progresses, individuals may develop involuntary eye movements (nystagmus).\n\nThere are more than 30 types of cone-rod dystrophy, which are distinguished by their genetic cause and their pattern of inheritance: autosomal recessive, autosomal dominant, and X-linked. Additionally, cone-rod dystrophy can occur alone without any other signs and symptoms or it can occur as part of a syndrome that affects multiple parts of the body.\n\nCone-rod dystrophy is a group of related eye disorders that causes vision loss, which becomes more severe over time. These disorders affect the retina, which is the layer of light-sensitive tissue at the back of the eye. In people with cone-rod dystrophy, vision loss occurs as the light-sensing cells of the retina gradually deteriorate.
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Recent clinical studies

Etiology

Inherited Retinal Dystrophy in Southeastern United States: Characterization of South Carolina Patients and Comparative Literature Review.
Griffith J 3rd, Sioufi K, Wilbanks L, Magrath GN, Say EAT, Lyons MJ, Wilkes M, Pai GS, Peterseim MMW
Genes (Basel) 2022 Aug 20;13(8) doi: 10.3390/genes13081490. PMID: 36011402Free PMC Article

Diagnosis

Inherited Retinal Dystrophy in Southeastern United States: Characterization of South Carolina Patients and Comparative Literature Review.
Griffith J 3rd, Sioufi K, Wilbanks L, Magrath GN, Say EAT, Lyons MJ, Wilkes M, Pai GS, Peterseim MMW
Genes (Basel) 2022 Aug 20;13(8) doi: 10.3390/genes13081490. PMID: 36011402Free PMC Article
A new novel nonsense mutation in AIPL1 in a LCA4 family.
Wan L, Xiang L, Wang H, Shi Y, Jiang D, Hao F, Huang L
Ophthalmic Genet 2019 Aug;40(4):380-384. doi: 10.1080/13816810.2019.1666878. PMID: 31576779

Prognosis

A new novel nonsense mutation in AIPL1 in a LCA4 family.
Wan L, Xiang L, Wang H, Shi Y, Jiang D, Hao F, Huang L
Ophthalmic Genet 2019 Aug;40(4):380-384. doi: 10.1080/13816810.2019.1666878. PMID: 31576779

Clinical prediction guides

A new novel nonsense mutation in AIPL1 in a LCA4 family.
Wan L, Xiang L, Wang H, Shi Y, Jiang D, Hao F, Huang L
Ophthalmic Genet 2019 Aug;40(4):380-384. doi: 10.1080/13816810.2019.1666878. PMID: 31576779
Evaluation of Italian patients with leber congenital amaurosis due to AIPL1 mutations highlights the potential applicability of gene therapy.
Testa F, Surace EM, Rossi S, Marrocco E, Gargiulo A, Di Iorio V, Ziviello C, Nesti A, Fecarotta S, Bacci ML, Giunti M, Della Corte M, Banfi S, Auricchio A, Simonelli F
Invest Ophthalmol Vis Sci 2011 Jul 29;52(8):5618-24. doi: 10.1167/iovs.10-6543. PMID: 21474771

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