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Leber congenital amaurosis(LCA)

MedGen UID:
137922
Concept ID:
C0339527
Disease or Syndrome
Synonyms: Congenital retinal blindness; LCA; Leber's amaurosis
SNOMED CT: Leber congenital amaurosis (193413001); Leber amaurosis (193413001); Leber's amaurosis (193413001); CRB - Congenital retinal blindness (193413001); Congenital retinal blindness (193413001)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Related genes: RD3, LCA5, RDH12, CEP290, NMNAT1, RPGRIP1, SPATA7, AIPL1, CRB1, LRAT, TULP1, RPE65, KCNJ13, IMPDH1, GUCY2D, CRX
 
Monarch Initiative: MONDO:0018998
OMIM® Phenotypic series: PS204000
Orphanet: ORPHA65

Definition

Leber congenital amaurosis (LCA) comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009). Genetic Heterogeneity of Leber Congenital Amaurosis LCA2 (204100) is caused by mutation in the RPE65 gene (RPE65; 180069) on chromosome 1p31. LCA3 (604232) is caused by mutation in the SPATA7 gene (609868) on chromosome 14q31. LCA4 (604393) is caused by mutation in the AIPL1 gene (604392) on chromosome 17p13. LCA5 (604537) is caused by mutation in the LCA5 gene (611408) on chromosome 6q14. LCA6 (613826) is caused by mutation in the RPGRIP1 gene (605446) on chromosome 14q11. LCA7 (613829) is caused by mutation in the CRX gene (602225) on chromosome 19q13. LCA8 (613835) is caused by mutation in the CRB1 gene (604210) on chromosome 1q31. LCA9 (608553) is caused by mutation in the NMNAT1 gene (608700) on chromosome 1p36. LCA10 (611755) is caused by mutation in the CEP290 gene (610142) on chromosome 12q21 and may account for as many as 21% of cases of LCA. LCA11 (613837) is caused by mutation in the IMPDH1 gene (146690) on chromosome 7q32. LCA12 (610612) is caused by mutation in the RD3 gene (180040) on chromosome 1q32. LCA13 (612712) is caused by mutation in the RDH12 gene (608830) on chromosome 14q24. LCA14 (613341) is caused by mutation in the LRAT gene (604863) on chromosome 4q32. LCA15 (613843) is caused by mutation in the TULP1 gene (602280) on chromosome 6p21. LCA16 (614186) is caused by mutation in the KCNJ13 gene (603208) on chromosome 2q37. LCA17 (615360) is caused by mutation in the GDF6 gene (601147) on chromosome 8q22. LCA18 (see 608133) is caused by mutation in the PRPH2 gene (179605) on chromosome 6p21. LCA19 (618513) is caused by mutation in the USP45 gene (618439) on chromosome 6q16. Perrault et al. (1999) provided a review of Leber congenital amaurosis, with emphasis on genetic heterogeneity. Wiszniewski et al. (2011) analyzed 13 known LCA genes in 60 LCA probands, and identified homozygous or compound heterozygous mutations in 42 (70%). In addition, a third disease-associated mutant allele at a second locus was identified in 7 (12%) of the 60 patients. Wiszniewski et al. (2011) stated that the significance of the third mutated allele was unknown, but suggested that mutational load might be important to penetrance of the LCA phenotype. Because LCA manifests very early in life and results in profound vision loss, patients with mutations in other syndromic or nonsyndromic eye disease genes may receive an initial diagnosis of LCA, prior to development of syndromic features or before more thorough phenotyping can be performed (see, e.g., Senior-Loken syndrome-5, 609254). [from OMIM]

Additional description

From MedlinePlus Genetics
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.

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.

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.

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.

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

Professional guidelines

PubMed

Sharon D, Wimberg H, Kinarty Y, Koch KW
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Recent clinical studies

Etiology

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Int J Mol Sci 2021 Apr 26;22(9) doi: 10.3390/ijms22094534. PMID: 33926102Free PMC Article
Hu ML, Edwards TL, O'Hare F, Hickey DG, Wang JH, Liu Z, Ayton LN
Clin Exp Optom 2021 May;104(4):444-454. Epub 2021 Mar 2 doi: 10.1080/08164622.2021.1880863. PMID: 33689657
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Diagnosis

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Therapy

Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, Goodspeed K, Gray SJ, Kay CN, Boye SL, Boye SE, George LA, Salabarria S, Corti M, Byrne BJ, Tremblay JP
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Prognosis

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Chiu W, Lin TY, Chang YC, Isahwan-Ahmad Mulyadi Lai H, Lin SC, Ma C, Yarmishyn AA, Lin SC, Chang KJ, Chou YB, Hsu CC, Lin TC, Chen SJ, Chien Y, Yang YP, Hwang DK
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Ophthalmic Genet 2000 Sep;21(3):135-50. PMID: 11035546

Clinical prediction guides

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Genes (Basel) 2020 Nov 27;11(12) doi: 10.3390/genes11121420. PMID: 33261050Free PMC Article
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Am J Ophthalmol 2017 May;177:44-57. Epub 2017 Feb 16 doi: 10.1016/j.ajo.2017.02.003. PMID: 28212877

Recent systematic reviews

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