Leber Congenital Amaurosis

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).
  
  

Inheritance

Autosomal recessive

Genes

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

Epidemiology

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. 

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 ataxia^80,81 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 models^20,115-118 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).

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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