ORPHA: 65; DO: 0110329;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q11.2 | Leber congenital amaurosis 6 | 613826 | Autosomal recessive | 3 | RPGRIP1 | 605446 |
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.
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.
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).
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 patients (6%). 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).
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.
Chung, D. C., Traboulsi, E. I. Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. J. AAPOS 13: 587-592, 2009. [PubMed: 20006823] [Full Text: https://doi.org/10.1016/j.jaapos.2009.10.004]
Dryja, T. P., Adams, S. M., Grimsby, J. L., McGee, T. L., Hong, D.-H., Li, T., Andreasson, S., Berson, E. L. Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am. J. Hum. Genet. 68: 1295-1298, 2001. [PubMed: 11283794] [Full Text: https://doi.org/10.1086/320113]
Gerber, S., Perrault, I., Hanein, S., Barbet, F., Ducroq, D., Ghazi, I., Martin-Coignard, D., Leowski, C., Homfray, T., Dufier, J.-L., Munnich, A., Kaplan, J., Rozet, J.-M. Complete exon-intron structure of the RPGR-interaction protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis. Europ. J. Hum. Genet. 9: 561-571, 2001. [PubMed: 11528500] [Full Text: https://doi.org/10.1038/sj.ejhg.5200689]
Khan, A. O., Al-Mesfer, S., Al-Turkmani, S., Bergmann, C., Bolz, H. J. Genetic analysis of strictly defined Leber congenital amaurosis with (and without) neurodevelopmental delay. Brit. J. Ophthal. 98: 1724-1728, 2014. [PubMed: 24997176] [Full Text: https://doi.org/10.1136/bjophthalmol-2014-305122]
Pawlyk, B. S., Smith, A. J., Buch, P. K., Adamian, M., Hong, D.-H., Sandberg, M. A., Ali, R. R., Li, T. Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIP. Invest. Ophthal. Vis. Sci. 46: 3039-3045, 2005. [PubMed: 16123399] [Full Text: https://doi.org/10.1167/iovs.05-0371]