The diagnosis of Leber congenital amaurosis (LCA) typically involves two major criteria: severe visual impairment in early infancy and severely affected electroretinogram (ERG). Other clinical findings that may be seen are oculo-digital sign, near-absent pupillary reactions (or paradoxical pupils), nystagmus, high hyperopia, and photophobia. The prevalence is 1 in 30,000 to 50,000 births. This condition is the most frequent cause of inherited blindness of childhood. Because it is usually autosomal recessive, LCA is more prevalent if consanguinity or community constriction is present.

The retina may appear normal initially, but other findings may include macular geographic chorioretinal atrophy (macular “coloboma”), bone spicule pigmentary clumping in the “mid periphery,” subretinal flecks, or pigmented nummular lesions at the retinal pigment epithelium (RPE) level (▶ Fig. 25.1). Optic nerve anomalies such as drusen may be seen. Some patients with LCA do not develop obvious fundus anomalies until later in life, but in early years have only subtle findings, including mild RPE changes, initial vessel attenuation, or internal limiting membrane irregularity. Franceschetti’s oculo-digital sign (eye poking and rubbing) may be repetitive and severe. Patients often have an enophthalmic appearance. There is an association between LCA and keratoconus, which may in part be related to eye rubbing, although it has also been described in patients with LCA without eye poking.

Although retinal gene therapy for LCA2 was initially shown to have positive benefit for patients with RPE65 mutations, long-term follow-up of treated patients indicates some progressive diminution of the areas of improved vision. Perhaps additional repeat injection will be needed.

25.2 Molecular Genetics

LCA is associated to mutations in 22 genes, including AIPL1, CEP290, CRB1, CRX, DTHD1, GDF6, GUCY2D, IFT140, IMPDH1, IQCB1, KCNJ13, LCA5, LRAT, NMNAT1, OTX2, RD3, RDH12, RPE65, RPGRIP1, SPATA7, and TULP1. The most common are summarized in ▶ Table 25.1.

Pathogenic variants in these genes typically produce nonfunctional or absent protein product. Deletions or duplications are rarely reported. Heterozygotes are typically asymptomatic although symptoms and ERG findings may be seen in carriers of mutation in GUCY2D and RPGR1P1. Nonpenetrance has been reported with mutations in NMNAT1. Autosomal dominant LCA has been reported with mutations in cone–rod homeobox (CRX). Variable expression may occur.

Although there is no pathognomonic genotype–phenotype correlation, there is some evidence to establish common associations. Patients with CRB1 pathogenic variants may have preserved para-arteriolar RPE, often seen best on intravenous fluorescein angiography. Some individuals with RPE65 mutations present with star-shaped maculopathy associated with hypopigmented RPE white dots. In addition, “macular coloboma” or progressive macular atrophic lesion with sharp borders has been seen with mutations in AIPL1, CRB1, and NMNAT1. The phenotype of LCA in patients with AIPL1 mutations can be relatively severe, with maculopathy and marked bone-spicule pigmentary changes, with a large proportion of individuals having keratoconus and cataract. Patients with RPGRIP1 mutations frequently progress to light perception or no light perception. These individuals are characterized by early photophobia. Other gene mutations associated with photophobia include GUCY2D, RPGRIP1, and AIPL1. Affected individuals with predominant night blindness may have mutations in CRB1, RPE65, TULP1, and CRX. Patients have mild hyperopia, transient improvement of visual acuity, macular atrophy with later severe progression, and may either have RDH12 or RPE65 mutations. Nevertheless, loss of visual acuity usually happens at an earlier age in those with RDH12 mutations. Patients with IQCB1 mutations usually have greater loss of rods rather than cones. In addition, these individuals may also present with renal dysfunction. Keratoconus has been associated with CRB1 and AIPL1 mutations.

Occasionally, LCA is associated with neurodevelopmental delay and intellectual disability, although some reports establish that these findings occur in up to 15% of patients. This is particularly true for CEP290 mutations. Other genes that when mutated cause LCA with developmental delay include GUCY2D and RPGR1P1

Patients with LCA usually do not have visual acuity better than 20/400. AIPL1, GUCY2D, CRX, and RPGRIP1 mutations have been associated with severely decreased visual acuities in the first year of life, whereas RPE65, RDH12, and CRB1 mutations present variable visual acuities. Patients who have better visual acuity may have a delayed onset of visual symptoms until after the first year of life.

25.3 Differential Diagnosis

Many of the genes associated with LCA phenotype have phenotypic heterogeneity. Alternative phenotypes are summarized in ▶ Table 25.2.

25.3.1 Early-Onset Retinitis Pigmentosa (Juvenile Retinitis Pigmentosa)

This condition has a later age of onset than LCA (night blindness before 10 years), presents with no nystagmus, and has a better preservation of central visual acuity than in LCA. The photopic component of ERG in early-onset RP is usually spared or mildly abnormal.

25.3.2 Achromatopsia (OMIM 216900)

Like LCA, the retinal appearance can be normal, with low vision and nystagmus. ERG shows no involvement of rod system.

25.3.3 Congenital Stationary Night Blindness (OMIM 310500)

Uncommonly, patients with complete congenital stationary night blindness (CSNB) may present with low vision. These patients (usually associated with NYX mutations) present nonprogressive findings, and the ERG rules out LCA.

25.3.4 Conorenal Syndrome (OMIM 266920)

Conorenal syndrome (OMIM 266920) comprises cone-shaped digital epiphyses, cerebellar hypoplasia, and early-onset retinal dystrophy.

25.3.5 Senior–Løken Syndrome (OMIM 266900)

This is an autosomal recessive condition comprising nephronophthisis and LCA. It can be caused by mutation in the NPHP4 gene (1p36), NPHP5 gene (IQCB1,3q21), NPHP6 gene (CEP290, 12q21), SDCCAG8 gene (1q44), WDR19 gene (4p14), or TRAF3IP1 gene (2q37). Nephronophthisis manifests as normal-size or small kidneys with increased echogenicity and usually progresses to renal failure. Approximately 15% of patients with nephronophthisis associated with CEP290 mutations also have central nervous system and/or ophthalmic involvement, overlapping Joubert syndrome, and Senior–Løken syndrome.

25.3.6 Joubert Syndrome (OMIM 213300)

This is a phenotypically and genetically heterogeneous group of disorders defined by hypoplasia of the cerebellar vermis with the neuroradiologic “molar tooth sign” (▶ Fig. 25.2), and associated neurologic symptoms and developmental delay. It may include LCA and renal abnormalities. More than 17 genes have been associated with Joubert syndrome.

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