Leber Congenital Amaurosis 6

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

RPGRIP1, CRX, CRB1, NMNAT1, RPE65, AIPL1, CEP290, IQCB1, LCA5, SPATA7, TULP1, KCNJ13, LRAT, IMPDH1, RD3, GUCY2D, RDH12, USP45, GDF6, MERTK, IFT140, PCYT1A, MPP5, ABCA4, CLUAP1, USH2A, SLC38A8, CDHR1, GRM6, RP2, AHI1, PDE6A, CNGB3, GIGYF2, ZFYVE26, NR2E3, RGS9, CRB2, LCA10, OTX2, CLTA, PTPRC, MYO7A, CNGA3, CCT2, GUCA1A, PRPH2, IMPG1, CABP4, GUCY2F, SLC7A14, GUCA1B, LPCAT1, HSD17B6, ENO2, CNTLN, PSMD13, PRPH, GUCY2EP, BCL2, MIR204, EGF, SP4, RPGR, NUB1, ADH7, NRL, TUB, ND4, FST, SLC19A2, PRPF8, PNPLA6, CILK1, NINL, SERPINF1, RPGRIP1L, MEF2C, TAP2, MEF2A, ELOVL4, IMPG2, PDE6B

Drugs

9-cis-Retinyl acetate, Adeno-associated viral vector serotype 8 containing the human AIPL1 gene, Adeno-associated viral vector serotype 8 containing the human GUCY2D gene

9-cis-Retinyl acetate, Adeno-associated viral vector serotype 8 containing the human AIPL1 gene, Adeno-associated viral vector serotype 8 containing the human GUCY2D gene, Adeno-associated virus serotype 8 containing the human RdCVF sequence and the human RdCVFL sequence, Adenovirus associated viral vector serotype 4 containing the human RPE65 gene, Adenovirus associated viral vector serotype 5 containing the human RPE65 gene, Adenovirus-associated viral vector serotype 2 containing the human RPE65 gene (AAV2-hRPE65v2 ), Antisense oligonucleotide complementary to the exonic splicer enhancer sequence at intron 26 of the centrosomal protein 290 pre-mRNA, Combination of three adeno-associated viral vectors of serotype 8 containing the 5'-, the body- and the 3'- coding sequences of human CEP290 fused to inteins, Recombinant adeno-associated viral vector serotype 5 encoding Staphylococcus aureus Cas9 endonuclease and two guide RNAs complementary to two regions of intron 26 of the CEP290 gene

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A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis-6 (LCA6) is caused by homozygous or compound heterozygous mutation in the RPGRIP1 gene (605446) on chromosome 14q11.

Description

Leber congenital amaurosis 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).

For a general description and a discussion of genetic heterogeneity of LCA, see 204000.

Clinical Features

Dryja et al. (2001) reported 3 patients with Leber congenital amaurosis. All experienced severe loss of central acuity, leading to nystagmus early in life, and had a degeneration of both rod and cone photoreceptors. One patient had nystagmus and vision limited to light perception since early childhood. Her fundi at age 26 years had moderate vascular attenuation and no intraretinal bone-spicule pigmentary deposits. Another patient had poor vision since early childhood; at age 15 years, he had nystagmus and vision limited to light perception. He was hyperopic, with a spherical equivalent of +2.6 averaged between the 2 eyes. His fundi showed vascular attenuation and bone-spicule pigmentary deposits. Full-field, rod-plus-cone ERG responses were nondetectable.

To investigate whether neurodevelopmental delay is a feature of strictly defined LCA, i.e., otherwise nonsyndromic with documentation of a nonrecordable ERG between 1 and 3 years of life, Khan et al. (2014) performed targeted next-generation sequencing with a panel of 14 LCA genes in 23 affected children from 19 endogamous and or consanguineous Saudi Arabian families from a retrospective case series. Five (22%) of the 23 children had concomitant neurodevelopmental delay, 2 with mutations in the RPGRIP1 gene and 3 with mutations in the GUCY2D gene (600179).

Molecular Genetics

Dryja et al. (2001) surveyed 57 unrelated patients who had Leber congenital amaurosis for mutations in RPGRIP1 and found recessive mutations involving both alleles in 3 (6%) patients. All 4 mutations (605446.0001-605446.0004) created premature termination codons and were likely to be null alleles.

Gerber et al. (2001) performed direct sequencing of the 24 coding exons of the RPGRIP1 gene in 2 consanguineous families with Leber congenital amaurosis in whom a genomewide screen had detected homozygosity at the 14q11 chromosomal region. A homozygous missense mutation and a homozygous null mutation were identified in the 2 families, respectively. Among 142 unrelated LCA patients, Gerber et al. (2001) found RPGRIP1 mutations in 8 patients (5.6%) (see, e.g., 605446.0007 and 605446.0008).

Animal Model

Pawlyk et al. (2005) found that recombinant adeno-associated virus (AAV)-mediated Rpgrip gene replacement preserved photoreceptor structure and function in the eyes of Rpgrip -/- mice. The authors suggested that gene replacement therapy might be effective in patients with LCA due to a defect in RPGRIP.