Clinical characteristics.

Leber congenital amaurosis (LCA), a severe dystrophy of the retina, typically becomes evident in the first year of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus. Visual acuity is rarely better than 20/400. A characteristic finding is Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing. The appearance of the fundus is extremely variable. While the retina may initially appear normal, a pigmentary retinopathy reminiscent of retinitis pigmentosa is frequently observed later in childhood. The electroretinogram (ERG) is characteristically "nondetectable" or severely subnormal.

Diagnosis/testing.

The diagnosis of LCA is established by clinical findings. Pathogenic variants in 17 genes are known to cause LCA: GUCY2D (locus name: LCA1), RPE65 (LCA2), SPATA7 (LCA3), AIPL1 (LCA4), LCA5 (LCA5), RPGRIP1 (LCA6), CRX (LCA7), CRB1 (LCA8), NMNAT1 (LCA9), CEP290 (LCA10), IMPDH1 (LCA11), RD3 (LCA12), RDH12 (LCA13), LRAT (LCA14), TULP1 (LCA15), KCNJ13 (LCA16), and IQCB1. Together, pathogenic variants in these genes are estimated to account for more than half of all LCA diagnoses. At least one other disease locus for LCA has been reported, but the gene is not known.

Management.

Treatment of manifestations: Treatment is supportive. Children and their parents should be referred to programs for the visually impaired child within their state or locality. Affected individuals benefit from correction of refractive error, use of low-vision aids when possible, and optimal access to educational and work-related opportunities.

Prevention of secondary complications: When possible children should be discouraged from repeatedly poking and pressing on their eyes.

Surveillance: Periodic ophthalmic evaluation for assessment of vision, trials of correction for refractive error, and, in those with residual vision, assessment of the presence of amblyopia, glaucoma, or cataract.

Genetic counseling.

Most often LCA is inherited in an autosomal recessive manner. At conception, each sib of an individual with recessively inherited LCA has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members is possible if the pathogenic variants in the family are known. Prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing. Rarely, LCA is inherited in an autosomal dominant manner as a result of a pathogenic variant in CRX; the possibility of autosomal dominant inheritance resulting from a de novo CRX pathogenic variant should be considered in individuals with LCA and no family history of the disease.

Clinical Diagnosis

The form of congenital or early-infantile blindness known as Leber congenital amaurosis (LCA) was first defined by Theodor Leber in 1869 and 1871 on the basis of clinical findings [Leber 1869, Leber 1871]. While no universally agreed-upon diagnostic criteria are available, the following features are highly suggestive:

• Blindness or severe visual impairment presenting in infancy, frequently before age six months. Individuals with LCA usually do not achieve visual acuity better than 20/400 [Cremers et al 2002].
• Extinguished or severely reduced scotopic and photopic electroretinogram (ERG). Normal ERG responses rule out a diagnosis of LCA. Visual evoked responses are variable.
• The oculo-digital sign, characterized by poking, rubbing, and/or pressing of the eyes [Fazzi et al 2003]. The oculo-digital sign has been claimed to be virtually pathognomonic for LCA; however, it can also be seen in other syndromic forms of severe vision impairment.
• Family history typically consistent with autosomal recessive inheritance

Individuals with LCA also frequently exhibit the following:

• Sluggish or near-absent pupillary reactions reflecting the severe retinal dysfunction
• Nystagmus that is pendular or roving and present in all positions of gaze
• High hyperopia (>5 diopters), which is thought to result from impaired emmetropization (the ability of the eye to accommodate to visual stimuli) as a consequence of early-onset visual impairment
• Photophobia
• Keratoconus, a noninflammatory, self-limiting axial ectasia of the central cornea. Keratoconus can significantly interfere with vision in normal individuals but usually does not become a vision-limiting factor in LCA.

Retinal findings. No retinal lesion is diagnostic of LCA or specific for certain genetic subtypes. Although fundus abnormalities are frequently present later in life, infants with LCA typically show either a normal fundus appearance or only subtle retinal pigment epithelial (RPE) granularity, retinal vessel attenuation and, uncommonly, various stages of macular atrophy.

Of note, three more specific retinal phenotypes can be observed:

• Preserved para-arteriolar retinal pigment epithelium (PPRPE) in individuals with CRB1 pathogenic variants
• "Translucent RPE," white dots, and a peculiar star-shaped maculopathy in individuals with RPE65 pathogenic variants
• A progressive macular atrophic lesion presenting in infancy or later in some individuals. Because of its sharply defined borders, this lesion has been at times called a “macular coloboma.” While it has been reported to occur with pathogenic variants in AIPL1 and CRB1, the correlation of this LCA phenotype is most prominent with pathogenic variants in NMNAT1 [Chiang et al 2012, Falk et al 2012, Koenekoop et al 2012, Perrault et al 2012].

Molecular Genetic Testing

Genes. Pathogenic variants in seventeen genes are known to cause Leber congenital amaurosis (LCA) (Table 1).

Testing Strategy

To establish the diagnosis in a proband. Hanein et al [2004] proposed a clinical flowchart using the presence or absence of photophobia, night blindness, hyperopia, macular/peripheral retinal abnormalities, and measurable acuity to help direct the order of genes selected for molecular studies.

• Multigene testing. Consider using a multigene Leber congenital amaurosis panel that includes many genes associated with LCA. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative variant or variants in any given individual also varies. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Carrier testing for autosomal recessive LCA for relatives at-risk requires prior identification of the pathogenic variants in the family. Note: Carriers are heterozygotes for these autosomal recessive disorders and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic testing for at-risk pregnancies require prior identification of the pathogenic variant(s) in the family.

Clinical Description

Leber congenital amaurosis (LCA) has retinal, ocular, and extraocular features and occasionally, systemic associations [Fazzi et al 2003].

Retina. The retina may appear normal initially; later, a variety of abnormalities may develop either in isolation or combination:

• "Macular coloboma"; not a true coloboma, but reflecting discrete chorioretinal degeneration and atrophy centered about the fovea
• "Bone-spicule" intraretinal pigment migration
• Widespread subretinal flecks resembling retinitis punctata albescens
• "Marbled" fundus
• Discrete pigmented nummular lesions at the level of the retinal pigment epithelium (RPE)
• Optic disc abnormalities: swelling, drusen formation, and peripapillary neovascularization

Oculo-digital sign. The characteristic extraocular sign in LCA is Franceschetti's oculo-digital sign, comprising three components: eye poking, pressing, and rubbing. It is not known why this behavior occurs. The major sequelum is enophthalmos, a physical defect in which the eye recedes into the orbit, presumably from atrophy of orbital fat. Keratoconus has been said to result from the repetitive trauma to the cornea, but others have suggested that this may be a feature of LCA itself.

Intellectual disability. Rarely, LCA is seen in association with neurodevelopmental delay, intellectual disability, and oculomotor apraxia-type behavior. However, many if not most of the historical reports date to earlier studies in which systemic phenocopies of LCA (see Differential Diagnosis) were not considered or ruled out. Still, some studies suggest that as many as 20% of children with LCA without associated anomalies develop intellectual disability [Schuil et al 1998]. Whether these individuals represent undiagnosed systemic disorders or a genetic subtype of LCA is unknown.

Prior to the identification of CEP290, none of the molecularly defined types of LCA was shown to be associated with intellectual disability or neurodevelopmental degeneration. Perrault et al [2007] reported a subset of individuals (15%) with CEP290-related LCA who have intellectual disability or autistic features, but no other extraretinal manifestations. Two of the six individuals in the study with intellectual disability or autism were later reclassified as having Joubert syndrome based on the presence of the “molar tooth” sign on MRI. In others, the MRI was apparently normal.

Visual impairment. Profound visual impairment is usually present from birth. One third of individuals with LCA have no perception of light. The visual impairment is generally stable or very slowly progressive. Occasionally in the early stages, a mild degree of visual improvement is observed. This improvement has been attributed to development of the central visual pathways rather than retinal maturation. Sustained improvements in acuity, visual field, and electrophysiologic measurements have been reported in one individual with a c.529delG pathogenic variant in CRX [Koenekoop et al 2002b]. Loss of visual acuity typically results from keratoconus, cataract, or evolving macular lesions.

Carriers. Carriers (heterozygotes) are usually asymptomatic; however, some heterozygotes for GUCY2D pathogenic variants have been shown to have mild cone dysfunction measured by decreased cone responses on electroretinogram [Koenekoop et al 2002a]. However, this is not associated with any findings on ophthalmologic examination and does not appear to interfere with vision.

Genotype-Phenotype Correlations

A number of genotype-phenotype correlations appear to have emerged.

GUCY2D (LCA1). Pathogenic variants in GUCY2D, which encodes retinal guanylyl cyclase 1 (RetGC), have been associated with a congenital severe cone-rod dystrophy characterized by photophobia, high hyperopia, and poor but stable vision with no visual improvement [Perrault et al 1999, Lorenz et al 2000, Hanein et al 2004]. However, Perrault et al [2005] described a man with early-onset RP resulting from the homozygous 4-bp pathogenic variant p.[His1079GlnfsTer54]+[His1079GlnfsTer54] in GUCY2D. The man has night blindness, peripheral vision loss, and preservation of central vision typical of RP. Unlike most null variants described in GUCY2D to date, p.His1079GlnfsTer54 is predicted to result in an elongation of the protein and residual protein function [Perrault et al 2005].

RPE65 (LCA2). Pathogenic variants in RPE65 have been associated with night blindness, some transient improvement in vision, and eventual progressive visual loss [Perrault et al 1999, Dharmaraj et al 2000b]. Lorenz found that four individuals with LCA and RPE65 pathogenic variants had measurable visual acuity at age six to ten years, despite severe visual impairment from infancy and nystagmus in three of the four [Lorenz et al 2000]. Photophobia was not a feature and all individuals had preservation of measurable peripheral vision. Rod ERG responses were undetectable, whereas cone ERG responses were detectable in early childhood.

Paunescu et al [2005] presented detailed follow-up data on three adult sibs with LCA suggesting that photophobia and progressive visual loss occur with age. Using a genotyping microarray, Zernant et al [2005] found that only five of 69 individuals with LCA (7%) with detectable pathogenic variants had an RPE65 genotype. This detection rate, lower than previous studies would predict, suggests that allelic variation in RPE65 may be more highly associated with early-onset severe retinal dystrophy than with classic LCA [Authors, personal observation].

Individuals with pathogenic variants in RPE65 may also demonstrate "translucent RPE," white dots, and a peculiar star-shaped maculopathy [Weleber et al 2011].

AIPL1 (LCA4). Dharmaraj et al [2004] studied 303 individuals with LCA and found that 26 probands (8.5% of their cohort) harbored homozygous or heterozygous pathogenic variants in AIPL1. Fourteen (54%) of these 26 individuals had at least one allele with the p.Trp278Ter pathogenic variant. The authors described the phenotype of LCA in these individuals and compared them to those observed and reported with LCA from pathogenic variants in GUCY2D, RPE65, CRX, CRB1, and RPGRIP1. The phenotype of LCA in individuals with AIPL1 pathogenic variants was found to be relatively severe, with maculopathy and marked bone-spicule pigmentary retinopathy in most and keratoconus and cataract in a large subset. The authors conclude that the visual loss associated with mutation of AIPL1 is similar in severity to that observed with mutation of GUCY2D. Pennesi et al [2011] reported a unique electroretinogram phenotype characterized by slow insensitive scotopic responses (SISR), which if present on testing may suggest this genetic form of LCA.

LCA5 (LCA5). In the Old River Brethren family originally linked to LCA5, severe visual dysfunction, nystagmus, the oculodigital sign, and a normal fundus were noted in all affected individuals in infancy. High hyperopia and attenuated retinal vasculature developed over time, and ERG recordings were severely reduced [Dharmaraj et al 2000a]. Den Hollander et al [2007] defined pathogenic variants within LCA5 in multiple unrelated families, all of whom presented with a similar, severe congenital retinal dystrophy. One of the families, reported earlier by Mohamed et al [2003], developed macular abnormalities including macular coloboma and atrophy. Renal, neurologic, cognitive, and hepatic functions have been normal across all affected families. Individuals with LCA5 have been shown to have spared photoreceptors, mostly in the macular region, that are adjacent to disorganized retina [Jacobson et al 2009].

RPGRIP1 (LCA6). Hanein et al [2004] described the following features as characteristic of RPGRIP1 pathogenic variants: early photophobia, hypermetropia less than +7 diopters, and visual acuity in the range of 20/400 to count fingers (CF). In follow up of individuals with LCA, Galvin et al [2005] found that visual acuity in children with pathogenic variants in RPGRIP frequently progresses to light perception (LP) or no light perception (NLP) within the first decade of life.

CRX (LCA7). Pathogenic variants in CRX have also been reported to be associated with stable vision [Dharmaraj et al 2000b] or even some modest improvement [Koenekoop et al 2002b]. Single or double base-pair deletions of the gene account for only the dominant forms of LCA, as a result of either an inherited dominant pathogenic variant or a de novo mutational event [Sohocki et al 1998, Rivolta et al 2001, Tzekov et al 2001, Perrault et al 2003].

CRB1 (LCA8). Night blindness is a constant feature of LCA resulting from CRB1 pathogenic variants. Jacobson et al [2003] found thick unlaminated retinas by optical coherence tomography (OCT) in individuals with LCA and CRB1 defects. Although some individuals with RP resulting from CRB1 pathogenic variants have the fundus appearance of preserved para-arteriolar RPE (PPRPE), no individuals with LCA resulting from CRB1 pathogenic variants have yet been reported to have PPRPE [den Hollander et al 2001].

CEP290 (LCA10). Two independent series of individuals with CEP290 pathogenic variants [den Hollander et al 2006, Perrault et al 2007] confirm a “typical” ophthalmologic LCA phenotype consisting of a severe infantile-onset cone-rod dystrophy with high hyperopia and severe ERG abnormalities. In addition, each series described a single individual with a reticular pigment epithelium in the peripheral retina with multiple white dots. This specific phenotype has not been reported with the other LCA-associated genes.

Extraretinal findings were described in a subset of individuals in Perrault’s study, and primarily included hypotonia and ataxia or intellectual disability and autistic behaviors. In fact, six of 40 families segregating CEP290 pathogenic variants were reported to have at least one affected individual with intellectual disability or autism. Two of those individuals were later reclassified as having Joubert syndrome on the basis of the classic "molar tooth" sign on MRI. Interestingly, a high degree of intrafamilial variability was observed with respect to the presence or absence of intellectual disability, leading the authors to suggest the possibility of a third allele or modifier gene in the development of cognitive disability in this subtype of LCA.

IMPDH1 (LCA11). Bowne et al [2006] described heterozygous, apparently de novo IMPDH1 pathogenic variants in two unrelated individuals with a diagnosis of LCA. IMPDH1 is a gene previously known to be associated with autosomal dominant retinitis pigmentosa. The clinical description of one of the individuals reported by Bowne et al [2006] fits the classic LCA phenotype; the other appears to have an early-onset retinal dystrophy better fitting the diagnosis of SECORD (see Differential Diagnosis). Additional studies must be undertaken to assess the prevalence of IMPDH1 pathogenic variants in the LCA population.

RDH12 (LCA13). In a further study of the individuals studied by Hanein et al [2004], Perrault et al [2004] identified 11 distinct pathogenic variants of RDH12 in 8/44 individuals with LCA characterized by congenital severe progressive rod-cone dystrophy. All eight with RDH12 pathogenic variants had a clinical course similar to that of individuals with RPE65 pathogenic variants: mild or absent hyperopia, transient improvement of visual acuity, and eventual macular atrophy with severe disease progression. Loss of visual acuity, however, occurred at an earlier age in those with RDH12 pathogenic variants than in those with RPE65 pathogenic variants. No RDH12 pathogenic variants were observed in persons with LCA presenting with the congenital stationary cone-rod dystrophy form of the disease.

IQCB1. Individuals with pathogenic variants in IQCB1 often have greater loss of rod function than loss of cone function. All newly diagnosed individuals with LCA should have testing for pathogenic variants in this gene and, if found, should undergo careful monitoring of renal function.

Keratoconus has been reported to occur in individuals with specific pathogenic variants in the CRB1 and AIPL1 genes [Hameed et al 2000].

Photophobia and night blindness. Hanein et al [2004] performed molecular screening on 179 unrelated individuals with LCA and reported the genotype-phenotype correlations on 85 who were found to harbor pathogenic variants on one or both alleles in one of seven LCA-associated genes. Frequencies of mutation in each gene were as follows:

• GUCY2D. 21.2% (38/179 families)
• CRB1. 10% (18/179)
• RPE65. 6.1% (11/179)
• RPGRIP1. 4.5% (8/179)
• AIPL1. 3.4% (6/179)
• TULP1. 1.7% (3/179)
• CRX. 0.6% (1/179)

The authors found that the presence of photophobia or night blindness at ages one and two years distinguished two groups:

• Those with photophobia constituted a cone-rod dystrophy class and were found to have pathogenic variants of GUCY2D, RPGRIP1, and AIPL1.
• Those with night blindness constituted a rod-cone dystrophy class and were found to have pathogenic variants of CRB1, RPE65, TULP1, and CRX.

Prevalence

The birth prevalence of LCA is two to three per 100,000 births. The condition is the most common cause of inherited blindness in childhood and constitutes more than 5% of all retinal dystrophies. LCA accounts for the cause of blindness in more than 20% of children attending schools for the blind.

LCA appears to be more prevalent when consanguinity is common [Sitorus et al 2003].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Leber congenital amaurosis (LCA), the following evaluations are recommended:

• Electroretinogram (ERG) to confirm the diagnosis and to assess retinal function
• Clinical genetic assessment to evaluate for the presence of systemic abnormalities
• Clinical genetics consultation

Treatment of Manifestations

Except for RPE65-related LCA (see Therapies Under Investigation), no substantial treatment or cure for LCA exists, and, thus, care is supportive. Parents should be referred to programs for the visually impaired child within their state or locality.

Affected individuals benefit from correction of refractive error, use of low-vision aids when possible, and optimal access to educational and work-related opportunities.

Prevention of Secondary Complications

Children should be discouraged from repeatedly poking and pressing on their eyes, although attempts to alter such behavior are not always successful.

Surveillance

Affected individuals should be periodically seen for assessment of vision, trials of correction for refractive error, and when residual vision is present, assessment of the presence of amblyopia, glaucoma, or cataract.

Rarely, vision appears to improve beyond expectations; in such cases, a repeat ERG is indicated.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

In a naturally occurring Briard dog model of LCA resulting from mutation of RPE65, gene therapy utilizing AAV-mediated RPE65 was shown to restore visual function, an effect that has been documented to last for more than five years [Acland et al 2005]. More than 50 dogs have now been treated, with sustained success in 95% of treated eyes. The results of three simultaneous Phase I clinical treatment trials of AAV-mediated RPE65 gene therapy in humans were recently reported [Bainbridge et al 2008, Cideciyan et al 2008, Hauswirth et al 2008, Maguire et al 2008]. Initial results demonstrated safety, and showed slight improvement in vision in both bright and dim light.

Clinical and laboratory studies suggest that persons with CEP290-related LCA may also be good candidates for gene therapy. Cideciyan et al [2008] studied the retinal architecture of CEP290-mutant mice and humans. In the mouse retina, dramatic retinal remodeling was evident by age four to six weeks. Cross-sectional imaging of affected human retinas performed using optical coherence tomography (OCT) indicated preservation of foveal cones. The relative sparing of foveal cone cells, despite severe visual dysfunction, suggests an opportunity for cell rescue.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Most often, Leber congenital amaurosis (LCA) is inherited in an autosomal recessive manner. Rarely, pathogenic variants in CRX causing LCA are inherited in an autosomal dominant manner.

Autosomal Recessive LCA – Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with Leber congenital amaurosis are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members of a proband. Sibs of the proband's parents are at a 50% risk of being carriers.

Autosomal Dominant LCA – Risk to Family Members

Parents of a proband

• Most children diagnosed as having autosomal dominant LCA have an affected parent.
• Occasionally a molecular diagnosis is made in the absence of family history. Such cases are the result of de novo pathogenic variants in CRX [Jacobson et al 1998, Sohocki et al 1998, Swaroop et al 1999, Rivolta et al 2001, Perrault et al 2003].

Sibs of a proband. The risk to sibs depends on the genetic status of the proband's parents:

• If one of the proband's parents is affected with LCA, the risk to sibs of inheriting the mutated allele is 50%.
• When neither parent of the proband is affected, the risk to sibs is negligible.

Offspring of a proband. Individuals with autosomal dominant LCA have a 50% chance of transmitting the mutated allele to each child.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for Leber congenital amaurosis are possible.

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Suggested Reading

• Koenekoop RK. RPGRIP1 is mutated in Leber congenital amaurosis: a mini-review. Ophthalmic Genet. 2005;26:175–9. [PubMed: 16352478]

Acknowledgments

Supported in part by Foundation Fighting Blindness, Research to Prevent Blindness, and the Grousbeck Family Foundation.

Revision History

• 24 May 2018 (ma) Retired chapter: covered in LCA/EOSRD Overview
• 2 May 2013 (me) Comprehensive update posted live
• 30 March 2010 (me) Comprehensive update posted live
• 12 October 2006 (me) Comprehensive update posted live
• 9 November 2005 (rw) Revision: RDH12 gene identified
• 7 July 2004 (me) Review posted live
• 30 December 2003 (rw, pf, kt) Original submission