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  • A Compendium of Inherited Disorders and the Eye, Oxford University Press

    OMIM Numbers

    • 204000 (LCA1), 204100 (LCA2), 604232 (LCA3), 604393 (LCA4), 604537 (LCA5), 613826 (LCA6), 613829 (LCA7), 613835 (LCA8), 608553 (LCA9), 611755 (LCA10), 613837 (LCA11), 610612 (LCA12), 612712 (LCA13), 613341 (LCA14), 613843 (LCA15), 614186 (LCA16), 614620 (IFT40), 609237 (IQCB1), 616787 (CLUAP1), 179605 (PRPH2).


    Autosomal recessive


    There are currently 20 retinal genes whose mutations cause the phenotype of LCA, accounting for about 70% of the cases, while the genes underlying the remaining 30% of patients await discovery.1 The causal LCA genes include GUCY2D (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), IQCB1, CLUAP1, PRPH2, KCNJ13, and IFT140. These genes encode retinal proteins that affect one of seven pathways, the disruption of each of which causes retinal degeneration:

    • The phototransduction cascade (GYCY2D, AIPL1, and RD3);
    • The retinoid cycle (RPE65, LRAT, and RDH12);
    • Retinal development (CRX);
    • The intraflagellar transport (SPATA7, LCA5, RPGRIP1, CEP290, TULP1, NPHP5, CLUAP1, and IFT140);
    • Photoreceptor structure (CRB1 and PRPH2);
    • Photoreceptor ion channels (KCNJ13);
    • Metabolic enzymes for cellular survival (IMPDH1 and NMNAT1).1


    Leber congenital amaurosis (LCA) is the second most common group of inherited retinal dystrophies after retinitis pigmentosa, accounting for about 5% of all retinal dystrophies. With an estimated prevalence ranging from 1 per 33,0002 to 1 per 81,000,3 LCA accounts for about 20% of legal blindness in children.4

    Clinical Findings

    LCA manifests itself in the first 6 months of life with significant visual loss and sensory, pendular nystagmus. Visual acuity (VA) in children with LCA varies significantly among patients with differing gene mutations and can be as low as no light perception (NLP). This variability has led in recent years to some confusion about terminology and the clinical diagnosis of this group of disorders. For example, patients with mutations in CRB1, LRAT, CEP290, or RPE65 may have VA better than 20/50 and may actually be diagnosed later in early childhood, and sometimes designated as having early-onset childhood retinal dystrophy or early-onset severe childhood retinal dystrophy, rather than LCA. There is a progressive decline in the visual function of all patients.5 The retinal phenotype in LCA is extremely variable and includes a relatively normal appearance (Figures 1 and 2); typical vascular attenuation and bone-spicule pigmentation (Figure 3); nummular pigmentation, maculopathy with atrophic changes (Figure 4), or colobomatous-like macular changes; thickening of the macula with sparing of the para-arteriolar retinal pigment epithelium (RPE) (Figure 5); and Coats-like exudative vasculopathy. Interestingly, there are phenotypic-genotypic correlations characteristic of some fundus changes. We have summarized the genetic and clinical characteristics of each genetic type of LCA in Table 1. Diagnostic findings such as non-recordable electroretinograms (ERGs) and specific optical coherence tomography (OCT) or fundus autofluorescence (FAF) findings add to the phenotypic-genotypic correlations (Table 1). Other clinical findings, such as refractive error, photophobia, photodysphoria, sluggish and poorly reactive pupils, oculodigital sign, keratoconus, and cataracts can be part of the phenotypic manifestations of LCA (Table 1).

    Figure 1. Fundus of a patient with LCA and GUCY2D mutations. Note normal appearance despite very poor vision.

    Figure 2. Myopic-looking fundus with slight attenuation of the vasculature in this young child with RPE65 mutations. Pigmentary changes develop with age in this type of LCA.

    Figure 3A.

    Figure 3B.

    Figure 3: A. Fundus photo of a patient with CEP290. Note attenuated vessels and peripheral pigmentary changes. B. Corresponding fundus autofluorescence picture demonstrating peripheral hypopigmented spots and a ring of hyperfluorescence surrounding the fovea.


    Figure 4. Older individual (30s) with RDH12 mutations and a macular atrophic lesion, as well as attenuated blood vessels and peripheral pigmentary changes.


    Figure 5. Right and left fundus photos of a young child with CRB1 mutations. Note prominence of the macular xanthophyll, thickening of the retina (see Figure 6), and preservation (darker areas) of the para-arteriolar RPE.

    Figure 6A.

    Figure 6B.

    Figure 6: A. OCT of a patient with CRB1 mutations showing thickening and disorganization of the retina in the macular area. B. OCT of another patient with CRB1 mutations revealing edematous changes commonly found in patients with CRB1 mutations. These may respond to treatment with topical carbonic anhydrase inhibitors. 

    Table 1: List of LCA causal genes, their encoded proteins, and their most important phenotypic manifestations

    Gene (LCA#)




    % of LCA Cases

    # Mutations

    Protein and Function (Pathway)

    Visual Function and Clinical Features

    Key Fundus Characteristics


    GUCY2D (LCA1)

    OMIM# 204000

    . AR

    . 17p13.1

    . 10-20%6

    . 1327

    Retinal guanylyl cyclase 1 (GC1)


    GC1 is a calcium-regulated module linked to retinal synaptic activity and thus phototransduction.8 Normally GC1 replenishes cGMP, but not in LCA. In GUCY2D-related LCA, the cells are low on cGMP, which results in a constant state of hyperpolarization.

    Severe but stable visual function loss (likely due to poor cone function).9 VA typically varies between 20/200 and LP.10 Color vision is also significantly reduced.11

    Significant photophobia, cataract, keratoconus13

    OCT: relatively preserved outer retinal structures14,15

    ERG: generally retains substantial rod function with poor cone function.14

    Initially, patients have normal fundus appearance. The fundus appearance changes with age and results in widespread chorioretinal atrophic changes by age 50.12

    Possible neurodevelopmental delay.16

    No other syndromic associations.

    RPE65 (LCA2)

    OMIM# 204100

    . AR

    . 1p31.3

    . 5-10%17

    . 13218

    Retinoid isomerohydrolase enzyme

    (Retinoid visual cycle)

    This enzyme normally isomerizes and hydrolyzes all-trans retinyl ester to 11-cis retinol each time a photon hits 11-cis retinal.

    Relatively good vision early in life (due to good residual cone function and alternative supply of 11-cis-retinal18) with a possible mild improvement in visual function temporarily. Specifically, patients have significant nyctalopia (poor rod function).19

    OCT: relatively preserved central macula surrounded by retina thinning/atrophy20,21

    FAF: reduced/absent autofluorescence
    signal, likely due to decreased levels of lipofuscin in the RPE layer.22

    Mild nystagmus (when present)

    Fundus exam is characteristic for a blond translucent appearance and whitish drusen-like deposits in about 90% of cases. Later in life, patients develop chorioretinal atrophy peripheral patches in 64% of cases10


    SPATA7 (LCA3)

    OMIM# 604232

    . AR

    . 14q31.3

    . 3%23

    . 1424

    Spermatogenesis-associated protein 7

    (Photoreceptor ciliary transport)

    SPATA7 localizes to the connecting cilium of the photoreceptors. It is responsible for protein trafficking across the photoreceptor connecting cilium, and for recruiting and localizing retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1) to the photoreceptor connecting cilium.

    OCT: preservation of the foveal inner/outer segment junction.25 FAF:  parafoveal hyperautofluorescent ring.25

    ERG: non-recordable scotopic and photopic.27 

    Infantile nystagmus. Moderate hypermetropic refractive error. Also cause juvenile autosomal recessive retinitis (arRP)

    Variable foveal involvement with diffuse peripheral retinal atrophic changes25 and attenuated vessels.26

    Midfacial hypoplasia with enophthalmos. Rare hearing loss and low sperm count.

    No syndromic associations.

    AIPL1 (LCA4)

    OMIM# 604393

    . AR

    . 17p13.2

    . <5%17

    . 507

    Aryl-hydrocarbon-interacting protein-like 1

    (Phototransduction and protein biosynthesis)

    AIPL1 is specific to rod photoreceptors in adult life only, showing a specific staining pattern extending from the inner segment to the synaptic junction in the outer plexiform layer.28 AIPL1 specifically targets processing of farnesylated proteins causing de-stabilization of phosphodiesterase 6 (PDE6), which is believed to be compromised in LCA, leading to early-onset retinal degeneration.29

    Significantly decreased but stable visual acuity, which ranges from LP to NLP in 43% of cases during their first decade.10

    ERG: pathognomonic pattern characterized by slow insensitive scotopic responses.29

    Nyctalopia. Mutations in AIPL1 also cause phenotypes of cone rod dystrophy (CRD) and juvenile arRP.

    Maculopathy that is specific for drusen-like deposits and variable pigmentary atrophic changes with patches of hypopigmentation and pigmentary clumping.10


    LCA5 (LCA5)

    OMIM# 604537

    . AR

    . 6q11-q16

    . 1-2%23

    . 1230


    (Photoreceptor ciliary transport)

    Lebercillin is located at the cilium between the inner and outer segments of photoreceptors.31 It interacts with intraflagellar transport (IFT) machinery and is involved in microtubule transport. Inactivation of Lebercillin mutations result in photoreceptor degeneration due to failure in outer segment formation.

    OCT: Preserved central island of outer nuclear layer (ONL) that decreases in thickness eccentrically with normal or reduced foveal ONL peak.34

    Nystagmus. Hyperopic refractive error

    Normal fundus in childhood progressing to various degree of atrophic changes32 including colobomatous macular changes.33

    Other ciliary defect as LCA5 is also expressed in upper (nasopharynx and trachea) and lower respiratory systems (lungs).9

    RPGRIP1 (LCA6)

    OMIM# 613826

    . AR

    . 14q11.2

    . 5%35

    . 717,36

    Retinitis pigmentosa GTPase regulator-interacting protein 1

    (Photoreceptor ciliary transport)

    Retinitis pigmentosa GTPase regulator (RPGR) and retinitis pigmentosa GTPase regulator-interacting protein (RPGRIP) are co-localized to outer segments of human rod and cone photoreceptors as well as neuronal cells such as amacrine cells.37 Both RPGR and RPGRIP proteins co-localize specifically to the photoreceptor connecting cilium, where they are essential for disk morphogenesis and regulation of actin cytoskeleton dynamic.38 Most mutations in RPGRIP1 result in protein truncation and complete functional loss.

    There is an initial severe decline in visual function (LP to NLP) that is stable afterward without significant worsening.39

    OCT: Preserved central foveal outer retinal structures surrounded by retinal laminar disorganization41

    Normal retinal
    appearance initially that progresses afterward to drusen-like pigmentary changes in 60% and 80% of cases.10,40


    CRX (LCA7)

    OMIM# 613829

    . AR (AD rare42)

    . 19q13.33

    . 1%


    Cone–rod homeobox

    (Photoreceptor morphogenesis)

    CRX is a transcription factor essential for both photoreceptor outer segment elongation and phototransduction cascade as it activates a specific sequence related to upstream processing of photoreceptor-specific genes.43

    Severe relatively stable vision loss (CF-NLP) in the first few months of life44,45

    ERG: markedly reduced or nondetectable.

    Infantile nystagmus; High hypermetropia; Photodysphoria; Keratoconus; Cataracts.9

    Diffuse pigmentary retinal changes and atrophic macular changes.45,46


    CRB1 (LCA8)

    OMIM# 613835

    . AR

    . 1q31.3

    . 10%17,39

    . 1667,47

    Protein crumbs homolog 1

    (Photoreceptor morphogenesis)

    The protein localizes to the inner segment of photoreceptors and is known to control the photoreceptor outer segment orientation and its adherens junctions with Muller cells by stabilizing the membrane-associated spectrin cytoskeleton.48

    Variable VA with possible mild temporary improvement followed by noticeable decline.9

    OCT: abnormally “unlaminated” thickened retina, almost resembling that of an immature state.49

    High hypermetropia (+5.00 to +10.00).50 RP with and without a Coats-like vasculopathy.

    Late-onset maculopathy, isolated AR foveal retinoschisis.51-54

    Nummular pigmentation maculopathy with preservation of the para-arteriolar RPE.


    NMNAT1 (LCA9)

    OMIM# 608553

    . AR

    . 1p36.22

    . Unknown prevalence and # of mutations

    Nicotinamide/nicotinic acid mononucleotide adenylyl transferase 1

    (Coenzyme NAD biosynthesis)

    The protein catalyzes the conversion of nicotinamide mononucleotide (NMN) and ATP into NAD+ as well as the cleavage of the latter.56 NMNAT1 is essential for cell survival and is reported to affect NAD protein folding of the resultant structure.57 

    Overall thinned retina.34

    Early onset extensive and progressive central maculopathy with colobomatous-like atrophic changes with outer hyperpigmented borders, as well as typical peripheral pigmentary changes, optic nerve pallor, and retinal blood vessel attenuation. This is possibly a developmental abnormality with lack of foveal formation and inner retinal laminae crossing the central retina.56


    CEP290 (LCA10, NPHP6)

    OMIM# 611755

    . AR

    . 12q21.32

    . 15-20%57

    . 1536,57

    Centrosomal protein Cep290

    (Photoreceptor ciliary transport)

    CEP290 interacts with photoreceptors building blocks, including pericentriolar material 1 (PCM1), to properly ensure centromere localization.58

    VA is a significant variable early and does not correlate with age in early infancy. Eventually, VA is reported to be extremely poor.57,59,60

    OCT: Preserved central island of ONL that decreases in thickness eccentrically with normal or reduced foveal ONL peak34,61

    Relatively normal in early childhood

    Nephronophthisis, hypotonia, ataxia, impaired olfactory function.60,62

    Joubert syndrome57,60

    Senior-Løken Syndrome 663

    IMPDH1 (LCA11)

    OMIM# 613837

    . AR

    . 7q32.1

    . 5%23

    . 136

    Inosine-5-prime-monophosphate dehydrogenase

    (Guanine synthesis)

    IMPDH1 is the rate-limiting enzyme for the de novo synthesis of guanine nucleotides.64

    Variable visual acuity

    Diffuse RPE mottling, no pigmentary deposits.65


    RD3 (LCA12)

    OMIM# 610612

    . AR

    . 1q32.3

    . <1%23

    . 86

    Retinal degeneration 3

    (Protein trafficking)

    RD3 is a chaperone protein required for the exit of guanylate cyclase from the endoplasmic reticulum of photoreceptors during   outer segments trafficking.66

    Poor vision with progressive decrease.9,67

    Initial hypermetropia progressing to myopia over the course of the disease.68 


    Atrophic macular lesions possibly progressing to a bull's-eye pattern with central yellow pigmentation.67,68


    RDH12 (LCA13)

    OMIM# 612712

    . AR

    . 14q24.1

    . 10%17,69

    . 657

    Retinol dehydrogenase 12

    (Retinoid visual cycle)

    RDH12 localizes to the inner segment base of photoreceptors70 and directs the transformation of 11-cis-retinol into 11-cis-retinal.71

    Variable visual acuity

    OCT: Severely disorganized retinal architecture corresponding to macular excavation with variable thinning or thickening of retinal layers.34

    Absent or very mild hypermetropia.72

    Coats-like exudative vasculopathy9

    Early childhood maculopathy characterized by pigmentary fishnet or reticular
    pattern with diffuse RPE atrophy. Intraretinal bone-spicules pigmentation develops during the disease course.69


    LRAT (LCA14)

    OMIM# 613341

    . AR

    . 4q32.1

    . <1%23

    . 1010

    Lecithin retinol acyltransferase

    (Retinoid visual cycle)

    LRAT catalyzes the esterification of all-trans-retinol in the RPE layer into all-trans-retinyl ester.

    Phenotype is similar to RPE65 deficiency

    Juvenile RP. Early-onset severe retinal dystrophy (EOSRD)

    Normal-appearing posterior pole with sharp peripheral hypopigmenation outside the arcades.73


    TULP1 (LCA15)

    OMIM# 613843

    . AR

    . 6p21.31

    . <1%23

    . 3110

    Tubby-like protein 1

    (Photoreceptor ciliary transport)

    TULP1 contributes to rhodopsin transport between the inner and outer segments of photoreceptor cells74 and stimulates the phagocytosis of RPE cells.

    Reading vision in early stages75

    OCT: Preserved central island of ONL that decreases in thickness eccentrically with normal or reduced foveal ONL peak34  FAF: hyperautofluorescent perifoveal ring75

    Nystagmus, hemeralopia, mild myopia; no photophobia75

    Funduscopic findings of patients with TULP1 LCA mutations vary significantly and include a normal fundus at early age, progressing to indistinct foveolar reflex and pronounced salt-and-pepper maculopathy later on with midperipheral RPE atrophy.75


    KCNJ13 (LCA16)

    OMIM# 614186

    . AR

    . 2q37.1

    . Unknown prevalence

    . 37

    Kir7 inwardly rectifying potassium channel


     KCNJ13, which is expressed in the apical microvilli of retinal pigment epithelia, is a potassium channel involved in maintaining the resting membrane potential near the potassium equilibrium potential.

    Poor night and reading visual function at an early age.76 Progressive visual deterioration affecting both peripheral and central vision. VA of CF reported by the first decade.76

    OCT: loss of outer retinal structures with RPE/Bruch membrane thinning.76,77

    Snowflake vitreoretinal degeneration4

    Severe retinopathy with nummular pigment and retinal degeneration and thinning.76,77



    OMIM# 614620

    . AR

    . 16p13.3

    . Unknown prevalence

    . 1110

    Intraflagellar transport 140 chlamydomonas homologue protein

    (Photoreceptor ciliary transport

    IFT140 is specifically involved in retrograde ciliary transport78

    Variable visual acuity

    OCT: IS/OS disruption and increased foveal thickness.

    FAF: hyperautofluorescent macular ring79


    Diffuse pigment clumps at posterior pole and mid-peripheral fundus79

    None isolated

    Mainzer-Saldino syndrome presents with retinal dystrophy (like LCA), severe renal disease, cerebellar ataxia, and skeletal dysplasia78

    Cono-renal syndrome includes early-onset LCA-like retinal dystrophy, cone-shaped phalangeal epiphyses of the hands, chronic renal failure, and ataxia80,81

    IQCB1 or NPHP5

    OMIM# 609237

    . AR

    . 3q13.33

    . Unknown prevalence

    . 248

    IQ motif containing B1 protein

    (Photoreceptor ciliary transport)

    IQCB1 has been reported to localize to retinal photoreceptors and to primary epithelial cells cilia.82

    Visual acuity ranging between 20/70 and NLP83

    ERG: markedly reduced or nondetectable83

     hypermetropia. Coats-like changes83

    Lobular pattern of hypo- and hyperpigmentation around the vascular arcades with retinal vessels straightening83


    Seniør-Loken syndrome 584


    OMIM# 616787

    . AR

    . 16p13.3 

    . Unknown prevalence

    . 17

    Clusterin-associated protein 1

    (Photoreceptor ciliary transport)

    CLUAP1 is found at the connecting cilium between the inner and outer segments of retinal photoreceptors.85 It is involved in IFT particle turnaround.

    Early onset severe visual deterioration to NLP.86

    ERG: extinguished.86





    OMIM# 179605

    . AR

    . 6p21.1

    . Unknown prevalence

    . 1127,87


    (Photoreceptor morphogenesis)

    Peripherin 2 localizes to the photoreceptor outer segment, where it serves as an adhesion molecule to stabilize the segment88

    Variable visual acuity

    OCT: Foveal globular lesions89

    adRP, digenic RP, autosomal dominant macular degeneration

    Peripheral and macular pigment deposits with central atrophic and chorioretinal sclerosis.89


    ERG, electroretinogram; FAF, fundus autofluorescence; NLP, no light perception; OCT, optical coherence tomography; VA, visual acuity


    LCA was defined in 1867 by Theodor Leber, and considered currently a pure ocular disease. Some patients, however, have a syndromic constellation of LCA-like ocular phenotype and systemic findings. These include:

    Joubert syndrome with oculo-renal disease (JBTS2: OMIM# 608091, JBTS3: OMIM# 608629, JBTS4: OMIM# 609583, JBTS5: OMIM# 610188, JBTS7: OMIM# 611560, JBTS9: OMIM# 612285, JBTS14: OMIM# 614424, JBTS20: OMIM# 614970) is a genetically heterogeneous group of disorders that are all autosomally inherited. Classic phenotypic manifestations include cerebellar and brainstem malformations (molar tooth sign), as well as hypotonia and developmental delay.90 However, patients often present with other findings, including juvenile-onset cystic nephronophthisis, early-onset LCA-like retinal dystrophy and either nystagmoid eye movement, episodic hyperpnea and/or apnea, or both.90 Mutations in the following genes have been reported to cause Joubert syndrome with oculo-renal disease:

    • TMEM216 (OMIM# 613277) causes JBTS2 (OMIM# 608091). Transmembrane protein 216 was found to localize to the ciliary base or adjacent basal body in the renal collecting duct and proximal renal tubular cells, as well as human retinal pigment epithelium.91 Functionally, TMEM216 is thought to be involved in cellular polarization and centrosomal apical docking.91 Mutations in TMEM216 can lead to ciliary shortening, disruption of vesicular trafficking92 and prevention of ciliogenesis.
    • AHI1 gene (OMIM# 608894) causes JBTS3 (OMIM# 608629). AHI1, which encodes Abelson helper integration site 1, has been reported to control ciliogenesis by regulating the formation of primary nonmotile cilia.93
    • NPHP1 gene (OMIM# 607100) causes JBTS4 (OMIM# 609583). NPHP1 (OMIM# 607100) which codes for nephrocystin 1. The latter belongs to a family of proteins involved in cellular polarization. Abnormal ciliary formation, delayed tight junction formation, and disorganized collagenous matrices were reported in the presence of dysfunctional nephrocystin proteins.94
    • CEP290 gene (also aka NPHP6 OMIM# 610142) causes JBTS5 (OMIM# 610188). Centrosomal protein Cep290 interacts with photoreceptors building blocks, including pericentriolar material 1 (PCM1), to properly ensure centromere localization.58
    • RPGRIP1L gene (NPHP8, OMIM# 610937) causes JBTS7 (OMIM# 611560). RPGRIP1L, which encodes for retinitis pigmentosa GTPase regulator-interacting protein 1-like protein or nephrocystin 8, localizes to the basal body and ciliary axoneme of primary cilia.95 It serves as a docking site for ciliary protein vesicular fusion-related processes.96
    • CC2D2A gene (OMIM# 612013) causes JBTS9 (OMIM# 612285). Coiled-coil and C2 domain-containing protein 2A localizes to the basal body of ciliary cells.97 It interacts with CEP290 in mediating ciliary transport mechanisms. Specifically, it serves as a docking site for ciliary protein vesicular fusion-related processes.96
    • TMEM237 gene (OMIM# 614423) causes JBTS14 (OMIM# 614424). Transmembrane protein 237 localizes to retinal photoreceptor outer segments and to the outer plexiform layer’s horizontal cells98 It regulates ciliogenesis by serving as a transition zone protein.99
    • TMEM231 gene (OMIM# 614949) causes JBTS20 (OMIM# 614970). Transmembrane protein 231 is part of a ring-like proteinaceous structure that restricts diffusion across the ciliary membrane. A dysfunctional TMEM231 affects ciliogenesis by altering ciliary growth.100

    Senior-Løken syndrome (SLSN3: OMIM# 606995, SLSN4: OMIM# 606996, SLSN5: OMIM# 609254, SLSN6: OMIM# 610189, SLSN7: OMIM# 613615, SLSN8: OMIM# 616307, SLSN9: OMIM# 616629) is a heterogeneous renal-retinal syndrome characterized by juvenile nephronophthisis (OMIM# 256100) and early-onset LCA-like retinal dystrophy.90,101,102 SLS1 is caused by mutations in NPHP1 (OMIM# 607100), which codes for nephrocystin 1. The latter belongs to a family of proteins involved in cellular polarization. Abnormal ciliary formation, delayed tight junction formation, and disorganized collagenous matrices were reported in the presence of dysfunctional nephrocystin proteins.94 Mutations in nephrocystin protein family other than NPHP1 were reported to cause SLS. These include:

    • NPHP3 gene (OMIM# 608002) causes SLSN3 (OMIM# 606995). Nephrocystin 3 is involved in regulating the composition of ciliary complexes.103
    • NPHP4 gene (OMIM# 607215) causes SLSN4 (OMIM# 606996). Nephrocystin 4 serves as a docking site for ciliary protein vesicular fusion-related processes.96
    • IQCB1 gene (NPHP5, OMIM# 609237) causes SLSN5 (OMIM# 609254). IQCB1 has been reported to localize to retinal photoreceptors and to primary epithelial cell cilia.82
    • CEP290 gene (NPHP6, OMIM# 610142) causes SLSN6 (OMIM# 610189). CEP290 gene (aka NPHP6 OMIM# 610142) causes JBTS5 (OMIM# 610188). Centrosomal protein Cep290 interacts with photoreceptors building blocks, including pericentriolar material 1 (PCM1), to properly ensure centromere localization.56
    • SDCCAG8 gene (NPHP10, OMIM# 613524) causes SLSN7 (OMIM# 613615). Serologically defined colon cancer antigen 8, or nephrocystin 10, was localized to the retinal photoreceptor transition zone in mouse104 It was reported to be involved in DNA repair processes.105
    • WDR19 gene (OMIM# 608151) causes SLSN8 (OMIM# 616307). WD repeat-containing protein 19, aka DYF-2 (in elegans) is expressed in retinal photoreceptors. It encodes for the intraflagellar transport 144 (IFT144) protein which is a subunit of IFT-A complex involved in retrograde ciliary transport.106,107
    • TRAF3IP1 gene (OMIM# 607380) causes SLSN9 (OMIM# 616629). It encodes for TNF Receptor Associated Factor 3-Interacting Protein 1, which is a subunit of IFT-B complex involved in anterograde ciliary transport.108

    Mainzer-Saldino Syndrome (MZSDS, OMIM# 266920) is an autosomal recessive syndrome characterized by renal and skeletal dysplasia, LCA-like retinal dystrophy, and cerebellar ataxia. MZSDS is part of the autosomal recessive skeletal ciliopathies known as short-rib thoracic dysplasia (SRTD) with or without polydactyly. The alternative designation of MZSDS is short-rib thoracic dysplasia 9 with or without polydactyly. MZSDS is caused by mutations in IFT40 (OMIM# 614620), which is a ciliary transport gene involved in retrograde transport (Table 1). MZSDS patients can display early onset LCA-like retinal dystrophy with visual impairment and undetectable ERG.78,109

    Conorenal syndrome (OMIM# 266920) includes early-onset LCA-like retinal dystrophy, cone-shaped phalangeal epiphyses of the hands, chronic renal failure, and ataxia80,81 This syndrome has been associated with pathologic mutations in IFT40 (OMIM# 614620). Fundus findings were reported as nonpigmented atypical retinal degeneration progressing to bone spicules deposition.110

    LCA Classifications

    LCA can be classified based on disease pathway, OCT findings, or retinal histopathology.

    LCA classification based on disease pathway

    There are currently 7 known, distinct pathways that are affected by one of the 20 mutant LCA genes. LCA disease pathway 1 involves molecules necessary for the phototransduction cascade, and includes the following genes: GYCY2D, AIPL1, and RD3. Disease pathway 2 is in the retinoid cycle and includes the RPE65, LRAT, and RDH12 genes. Disease pathway 3 includes the retinal transcription factor, which includes CRX. Disease pathway 4 involves intra-flagellar transport (IFT), and includes mutations in SPATA7, LCA5, RPGRIP1, CEP290, TULP1, NPHP5, CLUAP1, and IFT140. CRB1 and PRPH2 are included in disease pathway 5, which is involved in photoreceptor morphogenesis. Disease pathway 6 is in metabolic enzymes for cellular survival and includes IMPDH1 and NMNAT1. Finally, disease pathway 7 is in photoreceptor ion channels and is represented by mutations in KCNJ13.

    LCA classification based on optical coherence tomography (OCT) findings

    According to Jacobson et al., 201634 there are four major retinal architecture categories of LCA:

    Type 1: Normal in vivo retinal architecture: LCA patients with GUCY2D mutations can display subnormal retinal and outer nuclear layer (ONL) thicknesses within the central foveal degrees and normal parafoveal thickness.1

    Type 2: Thickened retina: This pattern, which is specific to CRB1 mutations, is characterized by a reduced foveal ONL, limited extra-central ONL, and thickened dysplastic or “unlaminated” retinal layers across the rest of the retina.1

    Type 3: Normal foveal architecture: This OCT laminar pattern is specific for a preserved central foveal island of ONL that decreases in thickness eccentrically. Mutations in RPE65 (LCA2), Lebercilin (LCA5), RPGRIP1 (LCA6), CEP290 (LCA10), and TULP1 (LCA15) have been associated with this phenotype.1

    Type 4: Severe macular atrophy or foveal maldevelopment: This OCT pattern is associated with LCA mutations displaying severe maculopathies, namely AIPL1 (LCA4), NMNAT1 (LCA9) and RDH12 (LCA13). Note that the colobomatous-like maculopathy seen with NMNAT1 (LCA9) mutations is possibly due to a congenital lack of foveal formation and inner retinal layers. All 3 mutations show a reduced central ONL. The parafoveal retinal thickness varies in AIPL1 (LCA4) and RDH12 (LCA13) patients but is significantly thinned in NMNAT1 (LCA9).1

    LCA classification based on retinal histopathology findings

    There are 3 distinct categories that have been described2 based on “pre-molecular testing” histological studies of LCA eyes from cadavers or blind painful enucleated eyes. In type 1, there is an abnormal embryological formation of photoreceptors corresponding to an aplastic process. Type 2 is characterized by a degeneration process in which there is early and progressive photoreceptor loss. In type 3, there is retinal dysfunction due to absence or dysfunction of key retinal biochemical messages despite relatively normal architecture. Not surprisingly, these 3 histological categories correlate well with the OCT-based classification. Specifically, type 1 may be represented by CRB1 mutations; type 2 may correlate well with RPGRIP1, LCA5, and RPE65 mutations; and type 3 may correlate with GUCY2D mutations.

    Therapeutic Considerations

    As in all other retinal dystrophies, the visual deterioration in LCA cannot be prevented and/or halted yet, although several very exciting and novel treatments are showing great promise in human clinical trials, including gene augmentation, oral drug therapy, and intraocular drugs. Early and precise clinical and molecular genetic diagnosis is the first step in the appropriate management of this group of diseases. A multi-disciplinary approach by ophthalmologists, ocular geneticists, and counselors, as well as retinal dystrophy support groups is the best means to efficiently frame this disease in its numerous facets, and assist patients with vocational, educational, and family planning. Monitoring and treating possible clinical associations, such as renal failure and hearing loss, is primordial to maximize patients’ quality of life.

    There have been significant advances in therapeutic modalities, including gene replacement, stem cell therapy, and pharmacologic therapies in a number of inherited retinal diseases. Gene replacement therapy using subretinal injection of genetically engineered adeno-associated virus (AAV) vectors has shown very promising results in several LCA animal models and humans: GUCY2D RetGC1 mouse models,111-113 RPE65 Briard dogs,114 and mouse models20,115-118 as well as AIPL1 knock-out mouse models,119 AAV-based gene replacement was shown to preserve and rescue photoreceptors (both rods and cones) and improve and restore retinal function. Based on this success, human clinical trials for LCA patients were undertaken globally and are at various stages of completion (Table 2).

    Table 2: List of ongoing and completed human clinical trials in LCA.124




    Target Gene






    Safety Study in Subjects With Leber Congenital Amaurosis

    Spark Therapeutics







    Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA) (OPTIRPE65)

    MeiraGTx UK II Ltd


    AAV2/5 OPTIRPE65





    Phase I Trial of Gene Vector to Patients With Retinal Disease Due to RPE65 Mutations (LCA)

    University of Pennsylvania







    Long-Term Follow-Up Gene Therapy Study for Leber Congenital Amaurosis OPTIRPE65 (Retinal Dystrophy Associated With Defects in RPE65)

    MeiraGTx UK II Ltd




    I and II



    Phase 1/2 Safety and Efficacy Study of AAV-RPE65 Vector to Treat Leber Congenital Amaurosis

    Applied Genetic Technologies Corp




    I and II



    Phase 1 Follow-on Study of AAV2-hRPE65v2 Vector in Subjects With Leber Congenital Amaurosis (LCA) 2

    Spark Therapeutics




    I and II



    Safety Study of RPE65 Gene Therapy to Treat Leber Congenital Amaurosis

    University College, London


    tgAAG76 (rAAV 2/2.hRPE65p.hRPE65)


    I and II



    Clinical Gene Therapy Protocol for the Treatment of Retinal Dystrophy Caused by Defects in RPE65 (RPE65)

    Nantes University Hospital




    I and II



    Safety Study in Subjects With Leber Congenital Amaurosis

    Spark Therapeutics







    Study to Evaluate QR-110 in Subjects With Leber's Congenital Amaurosis (LCA) Due to the c.2991+1655A>G Mutation (p.Cys998X) in the CEP290 Gene

    ProQR Therapeutics




    I and II

    Approved, not yet started


    Repeated Treatments of QLT091001 in Subjects With Leber Congenital Amaurosis or Retinitis Pigmentosa (Extension of Study RET IRD 01)

    QLT Inc.

    RPE65, LRAT






    Safety/Proof of Concept Study of Oral QLT091001 in Subjects With Leber Congenital Amaurosis (LCA) or Retinitis Pigmentosa (RP) Due to Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT) Mutations

    QLT Inc.

    RPE65, LRAT






    Presently, 3 phase I, 3 phase I/II and 1 phase III clinical trials in humans are being undertaken for RPE65-related patients using subretinal AAV gene replacement (Table 2). Furthermore, 2 phase I/II clinical trials have been completed. The data collected from these clinical investigations showed that AAV gene replacement is definitely safe but variably efficacious. Some studies have shown that the proposed treatment may not be sustainable, due to persistent progression of the retinal degeneration despite functional improvement in selected participants.121-124

    Oral substitutes of key components of the visual pathway have been clinically tested and have been shown to be safe and efficacious in children and adults with RPE65 and LRAT mutations.125,126 The 2 phases I/II clinical trials using a synthetic prodrug precursor to 9-cis-retinal, QLT091001, showed both significant enlargement of the kinetic visual field and improvement in visual acuity in 44% and 67% of participants, respectively.126 A phase III trial with the same agent is being planned.

    Finally, human embryonic stem cell (hESCs) therapy holds future promise as it aims to regenerate dysfunctional RPE cells. Currently, 2 human phase I/II stem cell clinical trials have demonstrated successful RPE integration of injected hESCs.127,128 The integration and transplantation of stem cells to the photoreceptor layer, which is needed for LCA therapy, is still in the preclinical stage.


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